EP1715873A1 - Nucleoside phosphonate derivatives useful in the treatment of hiv infections - Google Patents

Nucleoside phosphonate derivatives useful in the treatment of hiv infections

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Publication number
EP1715873A1
EP1715873A1 EP05723285A EP05723285A EP1715873A1 EP 1715873 A1 EP1715873 A1 EP 1715873A1 EP 05723285 A EP05723285 A EP 05723285A EP 05723285 A EP05723285 A EP 05723285A EP 1715873 A1 EP1715873 A1 EP 1715873A1
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EP
European Patent Office
Prior art keywords
compound
methyl
amino
purin
oxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP05723285A
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German (de)
French (fr)
Inventor
Devron R. Averett
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LG Chem Ltd
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LG Life Sciences Ltd
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Publication of EP1715873A1 publication Critical patent/EP1715873A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to a method for treating HIV infections comprising the administration of a nucleoside phosphonate derivative represented by the following formula (1):
  • R 1 , R 2 , R 3 , R 7 and R" independently of one another represent hydrogen, halogen, hydroxy, amino, C j -CVall-yl, C 2 -C 6 -alkenyl, C r C aIkyIammo, Cj-Cj-aminoalkyl, or C j - - -dkoxy
  • R and R 5 independently of one another represent hydrogen, or represent Cj-Q-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C r C 4 -alkoxy, phenoxy, Cr-C-o-pbe ⁇ ylalkoxy and C,- C 5 -acyloxy, or represent C,-C 7 -acyl, C 6 -C 12 -aryl or optionally substituted carbarnoyl, or represent -(CH ⁇ m-OC ⁇ O)-.* 6 wherein m denote
  • C j - -cyeloalkyl or 3 to 6- ⁇ .e ⁇ -bered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen,
  • -SiH(Z>, or Si(Z>, wherein Z represents hydrogen, hydroxy or halogen, or represents C r C 7 - alkyl, Cj-C 3 -aIkoxy, allyl, hydroxy-C ⁇ -C 7 -aJkyl, Cj-C 7 -aminoal-cyl or phenyl, Q repiesents a group having the following formula: wherein X 1 , X 2 , X 3 and X 4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent Cj-C 7 -a-kyl, C,-C r aIkoxy, allyl, hydroxy-Ci-CVa-kyl, pbenyl or phenoxy each of which is optionally substituted by nitro or C,-C 5 -a-koxy 5 or represent C 6 -C ] o-arylthio which is optionally substituted by nitro, amino, C,-C ⁇ -
  • Purine or pyrimidine derivatives have anti-cancer and antiviral activities, and more than 10 kinds of the compounds including AZT, 3TC and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidopovir has been commercialized as an antiviral agent and many compounds including PMEA and PMPA now entered into the step of clinical trials. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity, and thus, it is still desired to develop a compound having no toxicity as well as a superior activity.
  • the prior researches for purine o ⁇ pyrimidine derivatives or acyclic nucleoside phosphonate derivatives as reported heretofore are as follows.
  • one object of the present invention is to provide the compound of formula (1) having a good use of antiviral agent, ⁇ pharmaceutically acceptable salts or isomers thereof. It is another object of the present invention to provide a process for the preparation of the compound of formula (1).
  • the compound of formula (1) according to the present invention is a type of nucleoside phosphonate derivative having a natural base, such as for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof:
  • R 1 , R 2 , R 3 , R 7 and R 8 independently of one another represent hydrogen, halogen, hydroxy, amino, C,-C 7 -alk l, Cj-CValkenyl, C,-Cj-alkylamino, C j -C j -aminoalkyl, or Cj-Cj- alkoxy, R 4 and R 5 independently of one another represent hydrogen, or represent C r G,-alkyl .
  • substituents selected -xom the group consisting of halogen (particularly, fluorine), Cj-C 4 -alkoxy, phenoxy, C j -C j o-phenylalkoxy and Cj- -acyloxy, or represent C,-C 7 -acyl, C 6 -C ]2 -aryl or optionally substituted carbamoyl, or represent -(CH 2 )m-OC( O)- 6 wherein m denotes an integer of 1 to 12 and R 6 represents C.-C ⁇ 2 -alkyl, C 2 -C 7 -alkenyl, C,-C 3 -alkoxy, Ci- -alkylamino, di(C,-C 7 - alkyl)amino, C 3 -C 6 -cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -
  • X 1 , X 2 , X 3 and 4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent C ⁇ -C 7 -alkyl, C C 5 -alkoxy, allyl, hydroxy-C ⁇ C T -alkyl, phenyl or phenoxy each of which is optionally substituted by nitro or Cj-Cj-alkoxy, or represent C 6 -C 10 ---rylthio which is optionally substituted by nitro, amino, C r C 6 -alkyl or C j -C,,- alkoxy, or represent C 6 -C ⁇ 2 -arylamino, C r C 7 -alkylamino, di(C,-C 7 -alkyl)amino, Cs-C ⁇ - f ⁇ ⁇ i cycloalkylamino o ⁇ a structure of Y V TM-v N T wherein n denotes an integer of 1 or 2
  • the compound of formula (1) according to the present invention may have one or more asymmetric carbon atoms in the structure depending on the kind of substituents, it can be present in the form of the individual enantiomers, diastereomers, or mixtures thereof including racemate. Further, when a double bond is included in the structure, it can be present in the form of E or Z isomer. Thus, the present invention also includes all of these isomers and their mixtures. Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt.
  • Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fur ⁇ aric acid, maleic acid, etc., or a salt with sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,, ⁇ aphthalenesulfonic acid, etc., particularly preferably with sulfiiric acid, methanesulfonic acid or ' hydrohalic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, ni
  • the preferred compounds are those wherein — represents single bond, R 1 , R z , R 3 , R 7 and R 8 independently of one another represent hydrogen, fluorine, hydroxy, C,-C r alkyl, Cj-Cj-alkenyl, -Cj-alkylamino, C,-C 1i -aminoalkyl 5 or Cj-Cj-alkoxy, R 4 and 5 independently of one another represent hydrogen, or represent C C 4 -alkyl optionally substituted by one or more substituents selected -xom the group consisting of fluorine, C]-C-,-alkoxy and phenoxy, or represent carbamoyl substituted by C j - j - alkyl, or represent denotes an integer of 1 to 12 and R* represents C,-C, 2 -alkyL C 2 -C 7 -alkenyl,- Cj-Cj
  • X' represents hydrogen, amino, hydroxy or halogen, or represents C,-C 7 -alkyl, C J -C J - alkoxy, hydroxy-C r C 7 -alkyl or phenoxy each of which is optionally substituted by nitro or Ci-Cj-alkoxy, or represents C 6 -C 1( ary-t--io which is optionally substituted by nitro, amino, C,-C 6 -alkyl or C C 4 -alkoxy, or represents C 6 -C 12 -aryIamino, C 1 -C 7 - alky] amino, di(Cj-C 7 -alkyl)amino, Gj-Cj-cycloalkylamino or a structure of Y ⁇ ⁇ .
  • TM TM» wherein n denotes an integer of 1 or 2 and Y 1 represents O, CH 2 or N-R (R represents d-Cy-a-kyl), and .
  • X 2 , X 3 and - ⁇ independently of one another represent hydrogen, an-ino, hydroxy, halogen, C,-C r alkyl, Cj-C j -alkoxy, or
  • SZSl represents single bond
  • R 1 , R 3 , - 7 and R* independently of one another represent hydrogen
  • R 3 represents hydrogen or m "e-thy-
  • R 4 and R s independently of one another represent t-bu-ylcarbonyloxymethyl, iso jpropoxycarbonyloxym ethyl or 2,2,2-trifluoroethyl
  • Y represents -O-
  • Q represents
  • X 1 represents hydrogen, hydroxy, ethoxy, 4-methoxyphenyIthi or 4- nitrophenylthio, and X 2 represents amino.
  • the compounds of the invention are useful as anti-viral agents, and in particular against Human immunodeficiency Virus (HIV).
  • HIV Human immunodeficiency Virus
  • the compound of formula (1) according to the present invention can be prepared by a process as explained below, and thus, it is another object of the present mvention to provide such a preparation process.
  • conditions of the process such as for example, reactants, solvents, bases, amounts of the reactants used, etc. are not restricted to those explained below.
  • the compound of the present invention may also be conveniently prepared by optionally combining the various synthetic ways described in the present specification or known in the arts, and such a combination can be easily performed by one of ordinary skill in the art to which the present invention pertains.
  • the compound of formula (1) of the present invention can be prepared characterized in that (a) a compound represented by the following formula (2):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R B and Y are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy, p-toluenesulfonyloxy or halogen, is reacted with a compound represented by the following formula (3):
  • R 1 , R 2 , R 3 , R 7 , R 8 , Y and L are defined as previously described, and R 9 and R 10 independently of one another represent optionally substituted alkyl, is reacted with the compound of formula (3) to produce a compound represented by the following formula (10):
  • R 1 , R 2 , R 3 , R 7 , R 8 , Y and Q are defined as previously described, or
  • R 1 , R 2 , R 3 , R 7 , R 8 , Y and Q are defined as previously described, and R 4 ' and R 5 " represent R 4 and R s with the exception of hydrogen, respectively, or further the compounds thus obtained are subjected to conventional conversions (see: USP 6,037,335, 5,935,946, and 5,792,756).
  • the reactions may be carried out in a solvent and in the presence of a base.
  • a solvent one or more selected from a group consisting of dimethylformamide, dichloromethane, tetrahydrofuran, chloroform, l-methyl-2-pyrrolidinone and dimethylacetamide can.
  • the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide, sodium amide, cesium carbonate and potassium bis(trimethylsilyl)amide can be mentioned.
  • the Lewis acid which can be used in the process variant (b) includes trimethylsilylhalide.
  • this compound is subjected to an ether-forming reaction with an alkylhalide in the presence of a base, or is treated with tb ' onyl chloride, oxalyl chloride or phosphorus pentachloride to produce a dichlorophosphonate derivative which is then reacted with a • suitable alcohol or amine to give the desired compound.
  • the phosphonate compound of formula (2) used as a starting material in the above process is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (2).
  • P 1 represents an alcohol-protecting group, preferably benzyl(Bn), tetrahydropyranyl(THP), t-butyldiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS), is reacted with ethyl magnesium bromide[C 2 HjMgBr3 or the corresponding alkyl magnesium bromide or alkyl magnesium chloride in the presence of titanium tetraisopropoxide[Ti(OiPr) 4 ], ( ii) the resulting cyclopropanol represented by the following formula (5):
  • the resulting product may be further separated and purified by usual work-up processes, such as for example, chromatography, recrystallization, etc. '
  • the compound of formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is another object of the present invention to provide a composition for the treatment of viral diseases, which comprises as an active ingredient the compound of formula (1), pharmaceutically acceptable salt, hydrate, solvate or isomer thereof together with the pharmaceutically acceptable carrier.
  • the active compound according to the present invention When used for clinical purpose, it is preferably administered in an amount ranging generally from 0.1 to lOOOOmg, preferably from 0.5 to lOOmg per kg of body weight a day.
  • the total daily dosage may be administered in once or over several times.
  • the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex or hygienic condition of the subject patient, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc.
  • the compound of the present invention may be administered in the form of injections or oral preparations.
  • Injections for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent.
  • Solvents which can be used for preparing injections include water, Ringer's fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic , acid may also be used for injections.
  • solid preparations for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation.
  • the solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent.
  • the active compound of formula (1) can be administered in combination with one or more substances selected from the known anti- cancer or antiviral agents.
  • preparations comprising the compound of the present invention are not restricted to those explained above, but may contain any substances useful for the treatment or prevention of cancers or viral diseases.
  • the following Preparations (1-35) and Examples (1-52) are disclosed by Choi et al. in International Publication No. WO 02/057288, pgs. 38-82, and are explicitly incorporated herein:
  • the title compound was prepared as follows. 50g(146 m ole) of ethyl 2- ⁇ [t- butyl(diphenyl)silyl]oxy ⁇ acetate was dissolved in 700mA of tetrahydrofuran(THF) and 30.0mA of titaniu tetraisopropoxide was added thereto. To the mixture was slowly added 290mA of propylmagnesiumcJ-loride(2.0M in THF) at -10 * C, and the reaction solution was stirred for 12 hours at room temperature. 200mA of saturated ammonium chloride was added to stop the reaction.
  • the tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 2000mA of n-hexane.
  • the n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42g of the title compound.
  • the ethanesulfonate thus obtained (430mg) was dissolved in 18mA of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto.
  • the reaction mixture was refluxed under heating over 4 hours. Saturated ammonium chloride was added to stop the reaction.
  • the carboxylic acid prepared in Preparation 14 (16g) was dissolved in dichloromethane, 10.8mA of oxalyl chloride was added dropwise, and 2 drops of dimethylformamide was added. The reaction mixture was stirred at room temperature for 3- hours and distilled under reduced pressure to give ethoxycarbonyl 1,1-cyclopropane carbonylchloride. This compound, not purified, was dissolved in 30mA of dimethylformamide and the resulting solution was cooled with water-ice. 36g of N--N 3 was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 300mA of water and 200mA of diethylether, and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound.
  • the carboxylate prepared in Preparation 15 (13.2g) was dissolved in diethylether, to which 1.3g of L1BH 4 dissolved in diethylether was slowly added dropwise.
  • the reaction misture was stirred at room temperature for 16 hours, and 50mA of methanol and 5 mA of IN HCI were added dropwise thereto.
  • the reaction mixture was stirred for 2 hours, the precipitate was removed by suction filtration, and the solvent in the filtrate was removed by distillation under reduced pressure.
  • the residue was purified by silica gel column to give benzyl l-(hydroxymethyl)cyclopropylcarbamate.
  • NM-KCDCI 3 ⁇ 0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H), 3.55- 3.80 (m, 2H), 5.10 (s, 2H), 7.24-7.45 (m, 11H), 7.61 (m, 4H)
  • the carbamate prepared in Preparation 16 (l.Og) was dissolved in ethanol, lOOmg of 10% Pd/C was added, and the reaction mixture was subjected to a hydrogenation under hydrogen atmosphere. • After the reaction was completed, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give l-( ⁇ [t-butyl(diphenyl)silyl3oxy ⁇ methyl)-N-methyIcycIopropaneamine.
  • the compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 U for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methyla inediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
  • Lithium aluminum hydride (LAH) 15.3g was dissolved in 39g of tetrahydrofuran, and 11.7g of the carboxylic acid prepared in Preparation 21 was slowly added dropwise at OV. The reaction solution was refluxed for 17 hours. The reaction was stopped by adding 30% HCI at room temperature and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give 8.2g of diol compound.
  • the compound prepared in Preparation 22 (2g) was dissolved in 50mA of dichloromethane, and 1.03g of N-methylmorpholine N-oxide and 103mg of tetrapropylammom'umperruthenate (TPAP) were added thereto at room temperature.
  • TPAP tetrapropylammom'umperruthenate
  • the reaction mixture was stirred for about 1 hour at room temperature and the reaction was stopped by adding 20mA of water.
  • the reaction solution was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 2.0g of aldehyde ' compound.
  • Tetraethylm ethylene diphosphonate (1.7g) was dissolved in 60mA of tetrahydrofuran (THF). At -78 U, 264mg of NaH was added, the resulting mixture was stirred for 20 minutes, and then 1.9g of the aldehyde compound as obtained above was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction was stopped by adding 20mA of water. The reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column to give 2.32g of the title compound.
  • the title compound was prepared as follows. 10g(29 mmole) of ethyl 2- ⁇ [t- butyl(diphenyl)silyl3oxy ⁇ acetate was dissolved in 100mA of tetrahydrofuran (THF) and 6.0 mA of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37 t of isobutylmagnesiumbromide(2.0M in THF) at -10U, and the reaction solution was stirred for 12 hours at room temperature. 50mA of saturated ammonium chloride was added to stop the reaction.
  • THF tetrahydrofuran
  • the tetrahydrofuran (THF) used as .a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500 mA of n-hexane.
  • the n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 5.0g of the title compound.
  • the resulting mixture was stirred for 20 minutes, and then 1.0 g of the ketone compound as obtained above was added.
  • the reaction mixture was stirred at room temperature for 1 hour and was stopped by adding 20mA of water.
  • the reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column to give 654mg of the title compound.
  • Example 3 The compound prepared in Example 3 (3.00g) was dissolved in 350mA of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine- carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto.
  • the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature.
  • the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50mA of water and 50mA of toluene to separate the organic layer.
  • the aqueous layer was extracted twice with 50mA of toluene.
  • the combined organic layers were concentrated under reduced pressure.
  • Example 1 The compound prepared in Example 1 (l.OOg) was dissolved in 150mA of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine- carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto.
  • reaction mixture When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature.
  • the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50mA of water and 50mA of toluene to separate the organic layer.
  • the aqueous layer was extracted twice with 50mA of toluene.
  • the combined organic layers were concentrated under reduced pressure.
  • Example 3 The compound prepared in Example 3 (41mg) was dissolved in 5mA of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to give 37mg(Yield 95%) of the title compound as a white solid.
  • Example 5 The compound prepared in Example 5 was reacted according to the same procedure as Example 2 to give the title compound.
  • ⁇ MR(CDCl 3 -d4) ⁇ 0.90 (m, 2H), 1.05 (m, 2H), 1.20 (m, 18H), 3.96 (d, 2H), 4.22 (s, 2H), 5.65 (m, 4H), 8.03 (s, IH), 8.69 (s, IH) ESI: 528 (M+l) + , C22H34N5O8P
  • 6-Chlorogu--nine derivative prepared in Preparation 6 (lOOmg) was dissolved in 10 mA of ethanol, 32mA of triethylamine and 53 mg of sodium methoxide were added, and the resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10mA of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified by silica gel column to give a compound wherein 6-position of guanine was substituted by ethoxy group.
  • Example 16 Synthesis of [(l- ⁇ [2-amino-6-(l-piperidinyl)-9r-f-purin-9-yI ⁇ methyl ⁇ cyclopropyl)oxy]methylphosphonic acid(Compound 39) the compound prepared in Preparation 6 (154mg) was dissolved in 20mA of ethanol, 0.049mA of triethylamine and 0.11mA of piperidine were added thereto, and the resulting mixture was heated under reflux for 38 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate.
  • Example 19 Synthesis of 3-[( ⁇ l-I(2-an-ino-9-r-T-purin ⁇ 9-yl)methyl]cycJopropyl ⁇ oxy) methyl) -9-metby--3,7-dioxo-2,4,6-trioxa-3 ⁇ s -phosphadec-l-yl 3-methylbutanoate (Compound 74) '
  • the compound prepared in Example 5 (lOO g) was dissolved in dimethylformamide (2mA) and then reacted with chloromethyl 3-methylbutyrate in the presence of triethylamine (3 equivalents) at room temperature for 24 hours.
  • the resulting product was purified by silica gel column to give the title compound in a yield of 1%.
  • Example 5 The compound prepared in Example 5 was reacted with chloromethyl butyrate 10 according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 24%.
  • Example 5 The compound prepared in Example 5 was reacted with chloromethyl isobutyrate according to the same procedure as Example 19 at room temperature for 24 hours. The5 resulting product was purified by silica gel column to give the title compound in a yield of 21%.
  • Example 22 Synthesis of 3-[( ⁇ l-[(2-amino-9-r-T-purin-9-yl)methyl]cyclopropyl ⁇ oxy) methyl] , -3,7-dioxo-7-(l-pyrroIidinyl)-2 5 4,6-trioxa-3 ⁇ s -phosphahept-l-yl pyrrolidinecarboxylate (Compound 80)
  • the compound prepared in Example 5 was reacted with chloromethyl 1- pyrrolidinecarboxylate. according to the same procedure as Example 19 at room temperature for 24 hours.
  • the resulting product was purified by silica gel column to give the title compound in a yield of 35%.
  • Example 5 The compound prepared in Example 5 was reacted with chloromethyl 1- piperidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 39%.
  • Example 5 The compound prepared in Example 5 was reacted with chloromethyl 4- orpholinecarboxylate " according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title. compound in a yield of 40%.
  • ⁇ N- ttKCDCla ⁇ 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H),.3.65 (b ⁇ n, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, AH), 8.07 (s, IH), 8.69 (s, IH ESI: 586 (M+l) + , C23H33N6010P
  • Example 25 The methylphosphonic acid prepared in Example 25 was reacted according to the same procedure as Example 2 to give the title compound.
  • ⁇ NMRCCDC-a ⁇ 0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s, 3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d, 2H), 7.48 (d, 2H), 7.88 (s, IH) ESI: 649 ⁇ M+1) + , C30H41N4O8PS
  • Example 27 Synthesis of ⁇ [l-( ⁇ 2-amino-6-[(4-methoxyphenyl)sulfanyl]-9- ⁇ --purin-9-yl ⁇ methyI)cyclopropyl]oxy ⁇ methylphosphonic acid(Compo ⁇ nd 96)
  • 6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 mA of methanol and 1.4g of triethylamine and 2.9g of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20mA of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-p ⁇ sition of guanine was substituted by 4-methoxyphenylthio group.
  • Example 5 The compound prepared in Example 5 (387mg) was mixed with 6mA of N-methyl- 2-pyrrolidone, and 300mg of triethylamine and 150mg of chloromethyl t-butyl carbonate were added. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10mA of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
  • Example 5 The compound prepared in Example 5 (lOOmg) was mixed with 5mA of N-methyl- 2-pyrroh'done, and 1 lOmg of triethylamine and 150mg of chloromethyl isopropylcarbonate were added. The reaction solution was stirred at 50 for 4 hours. The reaction was stopped by adding 10mA of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
  • Example 37 Synthesis of ( ⁇ l-[(2-amino-9-r-T-purin-9-yJ)methyI]-2,2-dimethylcyclopropyI ⁇ oxy)metbylpbosphonic acid(Compo ⁇ nd 147)
  • the compound prepared in Preparation 32 was reacted according to the same procedure as Example 5 to give a compound wherein 6-position of guanine was reduced by hydrogen.
  • Example 46 Synthesis of 2- ⁇ l-[(6-amino-9---- r -purin-9-yl)methyI]cyclopropyl ⁇ propyl phosphonic acid(Compo ⁇ nd 143) « The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 5 to give the title compound.
  • Example 2 To the methylphosphonic acid prepared in Example 1 (150mg) was added dropwise dichloromethane, 0.73mA of - N-diethyltrimethylsilylamine was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. Oxalyl chloride (0.15mA) and 2 drops of dimethylformamide were added to the reaction vessel. The mixture was stirred for further 2 hours and the solvent was removed by distillation under reduced pressure. To the residue were added 10mA of pyridine and 2mA of trifluoroethanol, which was then reacted under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
  • Example 5 The compound prepared in Example 5 was reacted- according to the same , procedure as Example 47 to give the title compound.
  • Example 25 The compound prepared in Example 25 was reacted according to the same procedure as Example 47 to give the title compound.
  • 'H NMR(CDC1 3 ) ⁇ 0.88 (m, 2H), 1.03 (m, 2H), 2.39 (s, 3H), 4.06 (d, 2H), 4.19 (s, 2H), 4.33 ( , AH), 4.76 (br.s, 2H), 7.22 (d, 2H), 7.50 (d, 2H), 7.82 (s, IH) ESI: 586 [M+HQ+, C21H22F6N5O4PS
  • Example 4 The compound prepared in Example 4 was reacted according to the same procedure as Example 47 to give the title compound.
  • Example 7 The compound prepared in Example 7 was reacted according to the same ' procedure as Example 47 to give the title compound.
  • Example 52 Synthesis of ( ⁇ l-[(2-amino-9-f-T-purin-9-yl)methyl]-2-methyIcycIopropyl ⁇ oxy) methylphosphonic acid(Compo ⁇ nd 98)
  • the 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 5 to give the title compound.
  • the compounds of formula 1 protect cells from the cytopathic effects of HIV infection. This activity was demonstrated in the following assay systems and Table 8. Cells.
  • the T-lymphoblastoid cell line CEM was used in this study to propagate HIV. The cells were maintained in RPMI 1640 growth medium supplemented with 10% fetal bovine serum plus antibiotics.
  • the CD4-expressing cell line used for HIV plaque assays, HT4-6C was made by transforming HeLa cells with the human CD4 gene as described in Chesebro and Wehrly, J. Virology, 62(10), 3779-3788 (1988).
  • DMEM Dulbecco modified eagle medium
  • DMEM Dulbecco modified eagle medium
  • Virus propagation The laboratory strain of HIV-1 (NL4-3) was grown in CEM cells. Virus stocks were prepared from cleared lysates of concentrated infected cells. At peak cytopathic effect (generally 5 days post-infection) culture supernatants were harvested and stored at - 80°C. Viral infectivity titers were determined in threefold endpoint dilution assays conducted in CEM cells (six wells per dilution). The 50% tissue culture infective dose (TCIDjo) was calculated using the Reed and Muench equation. Plaque titration using HT4-6C.
  • TCIDjo tissue culture infective dose
  • DMEM fetal bovine serum plus antibiotics
  • Monolayers were infected with 10-fold dilutions of cell-free NL4-3 virus in 0.2 ml of DMEM and were incubated for 1 h at 37°C to allow virus adsorption. Following this, 0.8 ml of DMEM containing 5% fetal bovine serum plus antibiotics was added to each well, and the cultures were incubated at 37°C for 2 to 3 days.
  • the monolayers were fixed with a 10% formaldehyde solution in phosphate-buffered saline and stained with 0.25% crystal violet in order to visualize virus plaques. Individual foci of multinucleated giant cells (plaques) are obvious when this staining procedure was used. Virus titers were evaluated from plaque numbers and were expressed as PFU per milliliter. Drug susceptibility assays. Plaque reduction assays were performed by infecting monolayers of HT4-6C cells with 300 to 300 PFU of virus per well in 24-well microdilution plates as described above.

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Abstract

The present invention relates to a method of treating HIV infections by administering a nucleoside phosphonate derivative represented by formula (I).

Description

Nucleoside Phosphonate Derivatives Useful in the Treatment of HIV Infections
TECHNICAL FIELD
The present invention relates to a method for treating HIV infections comprising the administration of a nucleoside phosphonate derivative represented by the following formula (1):
in which — represents single bond or double bond, R1, R2, R3, R7 and R" independently of one another represent hydrogen, halogen, hydroxy, amino, Cj-CVall-yl, C2-C6-alkenyl, CrC aIkyIammo, Cj-Cj-aminoalkyl, or Cj- - -dkoxy, R and R5 independently of one another represent hydrogen, or represent Cj-Q-alkyl optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), CrC4-alkoxy, phenoxy, Cr-C-o-pbeπylalkoxy and C,- C5-acyloxy, or represent C,-C7-acyl, C6-C12-aryl or optionally substituted carbarnoyl, or represent -(CH^m-OC^O)-.*6 wherein m denotes an integer of 1 to 12 and 6 represents C,-C12-alkyl, C2-C7-alkenyl, C,-Cra!koxy, C,-C7-aIkylamino, diζCi-C,- a-kyl)amino. Cj- -cyeloalkyl, or 3 to 6-π.eπ-bered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -0-, -S-, -CH(Z>, =C(Z)-, -N(Z)-, =N-,. -SiH(Z>, or =Si(Z>, wherein Z represents hydrogen, hydroxy or halogen, or represents CrC7- alkyl, Cj-C3-aIkoxy, allyl, hydroxy-Cι-C7-aJkyl, Cj-C7-aminoal-cyl or phenyl, Q repiesents a group having the following formula: wherein X1, X2, X3 and X4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent Cj-C7-a-kyl, C,-CraIkoxy, allyl, hydroxy-Ci-CVa-kyl, pbenyl or phenoxy each of which is optionally substituted by nitro or C,-C5-a-koxy5 or represent C6-C]o-arylthio which is optionally substituted by nitro, amino, C,-Cβ-alkyl or C,-C4- alkoxy, or represent Cβ-C,2---rylamino, CrC7-al--ylamino, diO- CT-alky aπi-no, GpCg- cycloalkylamino or a structure of yOS>»-- wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R R represents Cι-C7-a--yl or C6-Cu-aryI), pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof.
BACKGROUND ART
Purine or pyrimidine derivatives have anti-cancer and antiviral activities, and more than 10 kinds of the compounds including AZT, 3TC and ACV have already been commercialized. Particularly, since acyclic nucleoside phosphonate derivatives show a potent antiviral effect, cidopovir has been commercialized as an antiviral agent and many compounds including PMEA and PMPA now entered into the step of clinical trials. However, the earlier developed compounds were not perfect in the aspects of toxicity or pharmaceutical activity, and thus, it is still desired to develop a compound having no toxicity as well as a superior activity. The prior researches for purine oτ pyrimidine derivatives or acyclic nucleoside phosphonate derivatives as reported heretofore are as follows. Patents; US 5817647; US 5977061; US5886179; US 5837871; US 6069249; WO 99/09031; WO96/09307; WO95/22330; US 5935946; US 5877166; US 5792756; Journals: International Journal of Antimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 464; Heterocycles 31(1990), 1571; J. Med Chem. 42 (1999), 2064; Pharmacology & Therapeutics 85 (2000), 251; Antiviral Chemistry & Chemotherapy 5 (1994), 57-63.; Bioorgcmic & Medicinal Chemistry Letters ]0 (2000) 2687-2690; Biochemical Pharmacology 60 (2000), 1907-1913; Antiviral Chemistry & Chemotherapy 8 (1997) 557- 564; Antimicrobial Agent and Chemotherapy 42 (1999) 2885-2892. DISCLOSURE OF INVENTION
Therefore, one object of the present invention is to provide the compound of formula (1) having a good use of antiviral agent, ■pharmaceutically acceptable salts or isomers thereof. It is another object of the present invention to provide a process for the preparation of the compound of formula (1).
It is still another object of the present invention to provide intermediates which are advantageously used for the preparation of the compound of formula (1).
BEST MODE FOR CARRYING OUT THE INVENTION
The compound of formula (1) according to the present invention, as represented below, is a type of nucleoside phosphonate derivative having a natural base, such as for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof:
in which ϊi::= represents single bond or double bond,
R1, R2, R3, R7 and R8 independently of one another represent hydrogen, halogen, hydroxy, amino, C,-C7-alk l, Cj-CValkenyl, C,-Cj-alkylamino, Cj-Cj-aminoalkyl, or Cj-Cj- alkoxy, R4 and R5 independently of one another represent hydrogen, or represent CrG,-alkyl . optionally substituted by one or more substituents selected -xom the group consisting of halogen (particularly, fluorine), Cj-C4-alkoxy, phenoxy, Cj-Cjo-phenylalkoxy and Cj- -acyloxy, or represent C,-C7-acyl, C6-C]2-aryl or optionally substituted carbamoyl, or represent -(CH2)m-OC(=O)- 6 wherein m denotes an integer of 1 to 12 and R6 represents C.-Cι2-alkyl, C2-C7-alkenyl, C,-C3-alkoxy, Ci- -alkylamino, di(C,-C7- alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -O-, -S-, -CH(Z)-, =C(Z , -N(Z>, =N-, -SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents C,-C7-alkyl, C2-C3-alkoxy, allyl, hydroxy-Cl-C7- alkyl, Cι-C7-a---inoalkyl or phenyl, Q represents a group having the following formula:
or N HγNH herein X1, X2, X3 and 4 independently of one another represent hydrogen, amino, hydroxy or halogen, or represent Cι-C7-alkyl, C C5-alkoxy, allyl, hydroxy-C^CT-alkyl, phenyl or phenoxy each of which is optionally substituted by nitro or Cj-Cj-alkoxy, or represent C6-C10---rylthio which is optionally substituted by nitro, amino, CrC6-alkyl or Cj-C,,- alkoxy, or represent C6-Cι2-arylamino, CrC7-alkylamino, di(C,-C7-alkyl)amino, Cs-Cβ- f~ \ i cycloalkylamino oτ a structure of YV ™-vNT wherein n denotes an integer of 1 or 2 and Y1 represents Os CH2 or N-R (R represents Ci-Cj-alkyl or C6-Cu-aryl).
Since the compound of formula (1) according to the present invention may have one or more asymmetric carbon atoms in the structure depending on the kind of substituents, it can be present in the form of the individual enantiomers, diastereomers, or mixtures thereof including racemate. Further, when a double bond is included in the structure, it can be present in the form of E or Z isomer. Thus, the present invention also includes all of these isomers and their mixtures. Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, furπaric acid, maleic acid, etc., or a salt with sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,, πaphthalenesulfonic acid, etc., particularly preferably with sulfiiric acid, methanesulfonic acid or'hydrohalic acid, etc.
Among the compound of formula (1) showing a potent phanriaceutical activity, the preferred compounds are those wherein — represents single bond, R1, Rz, R3, R7 and R8 independently of one another represent hydrogen, fluorine, hydroxy, C,-Cralkyl, Cj-Cj-alkenyl, -Cj-alkylamino, C,-C1i-aminoalkyl5 or Cj-Cj-alkoxy, R4 and 5 independently of one another represent hydrogen, or represent C C4-alkyl optionally substituted by one or more substituents selected -xom the group consisting of fluorine, C]-C-,-alkoxy and phenoxy, or represent carbamoyl substituted by Cj- j- alkyl, or represent denotes an integer of 1 to 12 and R* represents C,-C,2-alkyL C2-C7-alkenyl,- Cj-Cj-alkoxy, C,-C7-alkylamino, di(Cι-Cr alkyl)amino, C3-C6-cycIoalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -O-, -S-, or -N(Z)-, wherein Z represents hydrogen, hydroxy, Cj-C7-alkyl, or hydroxy-Ci-Cj-alkyl, Q represents a group having the following formula:
wherein
X' represents hydrogen, amino, hydroxy or halogen, or represents C,-C7-alkyl, CJ-CJ- alkoxy, hydroxy-CrC7-alkyl or phenoxy each of which is optionally substituted by nitro or Ci-Cj-alkoxy, or represents C6-C1( ary-t--io which is optionally substituted by nitro, amino, C,-C6-alkyl or C C4-alkoxy, or represents C6-C12-aryIamino, C1-C7- alky] amino, di(Cj-C7-alkyl)amino, Gj-Cj-cycloalkylamino or a structure of Y^ Γ . ™» wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2 or N-R (R represents d-Cy-a-kyl), and . X2, X3 and -^independently of one another represent hydrogen, an-ino, hydroxy, halogen, C,-Cralkyl, Cj-Cj-alkoxy, or
Most preferred compounds are those wherein SZSl represents single bond, R1, R3, -7 and R* independently of one another represent hydrogen, R3 represents hydrogen or m "e-thy-, R4 and Rs independently of one another represent t-bu-ylcarbonyloxymethyl, iso jpropoxycarbonyloxym ethyl or 2,2,2-trifluoroethyl, Y represents -O-, Q represents
X1 represents hydrogen, hydroxy, ethoxy, 4-methoxyphenyIthi or 4- nitrophenylthio, and X2 represents amino.
The compounds of the invention are useful as anti-viral agents, and in particular against Human immunodeficiency Virus (HIV).
Typical examples of the compound of formula (1) according to the present invention are described in the following Tables 1 and 7.
Table la COM. COM. STRUCTURE STRUCTURE NO. NO.
Table 2a
able 2c
Table 2e
Table 4
Table 5
Table 7
More particularly preferable compounds among the compounds described in the above Tables 1 and 7 are as follows: ({ l-[(6---mind-9-y-purin-9-yl)methyl]cyc]opropyl}oxy)methylphosphonic acid
(Compound 1); 3-[({l-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl- 3.7-dioxo-2,4.6-trioxa-3λ3-phosphanon-l-y] pivalate(Compoυnd 2); ({l-[(2---mino-6-chloro-9H-pur-n-9-yl)methyl]cyc]opropyl}oxy)methylρhosphonic acid(Compound 3); 3-[({l-[(2-amino-6-cl-loro-9-ry-purin-9-yl)methyl]cyclopropyl}oxy)methyl3-8,-.- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 4); ({ 1 -[(2-amino-6-hydroxy-9-f7-purin-9-yl)methyl]cyclopropyl} oxy)methyl phosphonic acid(Compound 5); 3-[({ 1 -[(2-amino-6-hydroxy-9-7-purin-9-yl)methyl3cyclopropyl} oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ -phosphanon-ϊ-yl pivalate(Compound 6); ({l-[(2-amino-6-fluoro-9-r- -purin-9-yI)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 7); 3 -[({ 1 -[(2-amino-6-fluoro-9--_r-purin-9-yl)methyl]cyclopropyl} oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 8); ({l-[(2---mino-9-ry-ρurin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (Compound 9); 3-[({ 1 -[(2---mino-9jy-purin-9-yl)methyl]cyclopropyl} oxy)metbyl]-8,8-dimethyl- 3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 10); ({l-[(2---mino-6-cyclopropyl--mino-9-&-pur-n-9-yl)methyl]cyclopropyl}oxy) meth- ylphosphonic acid(Compound 11); 3-[({l-[(2-amino-6-cyclopropylamino-9-r7-purin-9-yl)methyl]cyclopropyl}oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-ρhosphanon-l-yl pivalate(Compound 12); [(l-{[2---m-no-6-(dimethylamino)-9H-purin-9« yl]methyl3cyclopropyl)oxy]methylphosphonic acid(Compound 15); 3-{[(l-{[2-amino-6-(dimethylamino)-9 f-punn-9-yl]methyl)cyclopropyl)oxy] methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 16); [(l-{[2---mino-6-(isopropyl--π-ino)-9-ff-purin-9- yl]methyl}cyclopropyl)oxy]methy]phosphonic acid(Compound 17); 3 - { [(1 - {[2-amino-6-(isopropy3amino)-9Ar-purin-9-yl]methyl } cycloρroρyl)oxy] methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 18); ({ 1 -[(2,6-diamino-9-7-purin-9-yι)methyl]cyclopropyl} oxy)methylphosphonic acid(Compound 19); 3-[({l-[(2.6-diamino-9ϋ'-purin-9-yl)methy3]cyclopropyl)oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4;6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 20); ({ 1 -[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl} oxy)methyl phosphonic acid (Compound 21); 3-[({l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 22); ({l-[(2---mino-6-ethoxy-9i-"-purin-9-yl)methyl]cycloproρyl}oxy)methyl phosphonic acid (Compound 23); 3-[({l-[(2-amino-6-ethoxy-9ir-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 24); ({1 -[(2-amino-6-methyl-9-?y-purin-9-yl)methyl]cyclopropy3} oxy)methyl phosphonic acid(Compound 25); 3-[({l-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 26); [(1 -{ [5-methyl-2,4-dioxo-3,4-dihydro-l (2H)- pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonic acid(Compound 31); 8,8-dimethyl-3-{[(l-{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyl}cyclopropyl)oxy]methyl}-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate (Compound 32); [(l-{[2-amino-6-(4-morpholinyl)-9-r7-purin-9-ylJmethyl}cyclopropyl)oxy]methyl
• phosphonic acid(Compρund 37); 3-{[(l-{[2-amino-6-(4-morpholinyl)-9-r7-ρurin-9-yl]methyl}cyclopropyl)oxy] met- hyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 38); bis(2,2,2-trifluoroethyl) ({ 1 -[(2-amino-6-hydroxy-9.tf-ρur-n 9-y-)metbyl] cyclopropyl } oxy)me-hylphosphonate (Compound 45); bis(2,2,2-trifluoroethyl) ({l-[(2---mino-6-chloro-9-^-purin-9-yl)methyl3 cyclopropyl} oxy)roethylphosphonate(Compound 46); bis(2,2,2-trifluoroethyl) ({ l-[(2,6-diamino-9#-p h-9-yl)methyl]cyclopropyl} . oxy)methylphosphonate(Compound 47); bis(2,2,2-triflυoroethy_) ({ 1 -[(6-amino-9H-purin-9-yl)methyl]cyclopropyl} oxy)methylphosphonate(Compoun 48); bis(2,2,2-trifluoroethyl) ({ 1 -[(2-amino-9-ff-purin-9-yl)methyl]cyclopropyl} oxy)methylphosphonate(Compound 49); bis(232,2-trifluoroethyl) ({ 1 -[(2-amino-6-dimethylamino-9H-purin-9-yl)methyl] cyclopropyl) oxy)methylphosphonate(Compound 52); bis(2,2,2-trifluoroethyl) ({ 1 -[(2-amino-6-isopropylamino-9i-'-purin-9-yl) methyl]cyclopropyl)oxy)methy]phosphonate(Compound 53); bis(2,2,2-tπ'flυoroethyl) ({l-[(2-amino-6-methoxy-9H-purin-9-yl)methyl3 cyclopropyl}oxy)methylphosph'onate(Compound 54); bis(2,2,2-trifluoroεthyl) [(l-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]rnethyl} cyc]opropyI)oxy]methylphosphonate(Compouαd 58); bis(2,2,2-trifluoroethyl) [(1 - { [2-amino-6-(phenylsulfanyl)-9H-ρurin-9-yl] methyl) cycloρropyl)oxy]methylphosphonate(Compound 61); bis(2,2,2-trifluoroethyl) {[l-({2^amino-6-[(4-methylphenyl)sulfanyl]-9-9- purin-9- yl)methyl)cycloproρyl]oxy}methylphosphonate(Compound 62); bis(2,2,2-trifluoroethyl) { [ 1 -({2-amino-6-[(4-methoxyphenyl)sulfanyl]- 9if-purin- 9-yl}metbyl)cyclopropyl]oxy}methylphosphonate(Compound 63); bis(2,2,2-trifluoroethyl) {[1 -({2-amino-6-[(4---itroρhenyl)sulfanyl]- 9#-purin-9- yl) methyl)cyclopropyl]oxy} methylphosphonate(Compound 64); [(l-{[2-amino-6-(phenylsulfany])-9/-'-purin-9-yl]methyl}cyclopropyl)oxy3methyl phosphonic acid(Compound 65); {[l-({2-amino-6-[(4-methylphenyl)sulfanyl3-9-¥-ρurin-9-yl}methyl)cyclopropyl] oxyjmethylphosphonic acid(Compound 66); 3-({[H{2-amino-6-[(4-methylphenyl)sulfanyI3-9i-r-purin-9-yl}methyl)cyclo propyl3oxy3methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate (Compound 68); bis{[(t-butoxycarbonyl)oxy]methyl}({l-[(2-amino-9-ζ -purin-9-yl)methyl]cyclo propyl } oxy)methylphosphonate(Compound 69); bis{[(isoproρoxycarbony])oxy]methyl)({l-[(2-ar--ino-9-H-purin-9- yl)methyl3cyclopropyl}oxy)methylphosphonate (Compound 70); bis{[(ethoxycarbonyl)oxy]methyl}({l-[(2-amino-9?-!'-purin-9-yl)methyl3cyclo proρyl}oxy)methylphosphonate (Compound 71); bis{[(isobutoxycarbonyI)oxy3methyl}({l-[(2-amino-9-r-T-purin-9-yl)methyl3cyclo propyl} oxy)methylphosphonate (Compound 72); 3-[({l-[(2-ar--ino-9--f-purin-9-yl)methyl3cyclopropyl}oxy)methyl3-9-methyl-3,7- dioxo-2,4,6-trioxa-3λ5-phosphadec- 1 -yl 3-methylbutanoate(Compound 74); 3-[({l-[(2---mino-9-y-purin-9-yl)methyl]cyclopropyl}oxy)methyl3-8-methyl-3,7- dioxo-2,4,6-trioxa-3λ5-phosph-ιnon-l-yl 2-methylpropanoate(Compound 78); 3 -({ [ 1 - {2-amino-6-[(4-methoxyphenyl)sulfany-]-9H-pur-n-9-yl } methyl)cyclo propyl]oxy}methyI)-8,8-dimethyl-3,7-dioxo-2,4,6-τrioxa-3λs-phosphanon-l-yl pivalate (Compound 79); 3-[({l-[(2-amino-9J -purin-9-yl)methyl]cycIopropyl}oxy)methyl]-3,7-dioxo-7-(l- pyrrolidinyl)-2,4,6-trioxa-3A5-phosphahept-l-yl l-pyrrolidinecarboxylate(Compound 80); 3-[({l-[(2-amino-9-y-purin>9-yl)methyl3cyclopropyl}oxy)methyl3-3,7-dioxo-7-(l- piperidinyI)-2,4,6-trioxa-3A5-phosphahept-l-yI l-piperidinecarboxylate(Compound 81); 3-[({l-[(2-amino-9ii'-purin-9-yl)methyl]cyclopropyl}oxy)methyl3-7-(4-morpholi- nyl)-3,7-dioxo-2,4,6-trioxa-3λ5-phosphahept-l-yl -morphoh'nec--rboxylate(Compound 82); bis{[(t-butoxycarbony3)oxy3methyl}[(l-{[2-amino-6-hydroxy-9-r-t"-purin-9-yl3 methyl} cyclopropyl)oxy3methylphosphonate(Compound 83); bis{[(isopropoxycarbonyl)oxy]methyl}[(l-{[2---mino-6-hy-lroxy-9-?--purin-9-yl3 methyl) cyclopropyl)oxy]methylphosphonate(Compound 84); bis{[(isopropoxycarbonyl)oxy3methyl}{[l-({2-amino-[6-(4-methoxyρhenyl) sulfanyl]-9-9r-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 85); 3-[({ 1 -[(2-amino-6-hydroxy-9-r7-purin-9-y3)methyl3cyclopropyl} oxy)methyl3-7- cyclopeπtyl-3,7-dioxo-2,4,6-trioxa-3λJ-phosphahept-l-yl cyclopentanecarboxylate (Compound 86); 3-({[l-({2-amino-[6-(4-nitrophenyl)su-fanyl]-9--J-purin-9-yl}methyl)cyclopropyl3 oxy} methyl)-8, 8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 87); bis{[(isopropo-^c--rbony])oxy3methyl}{[l-({2---n-ino-[6-(4-nitrophenyl)sulfanyI3- 9iT-purin-9-yl} methyl)cyclopropyl]oxy} methylphosphonate(Comρound 88); bis{[(isopropoxycarbonyl)oxy3methyl}({l-[(6-amino-9-r7-purin-9-yl)methyl]cyclo- propyl}oxy)methylphosphonate(Compound 89); 3-[({l-[(6-amino-9-?7-purin-9-yl)methyl3cyclopropyl}oxy)methyl]-9-methyl-3,7- dioxo-2,4,6-trioxa-3λ5-phosphadec-l -yl 3-methylbutanoate(Compound 90); 3-[({l-[(6-amino-9H-purin-9-yl)methyl3cyclopropyl}oxy)methyl3-7-cyclopentyl- 3,7-dioxo-2,4,6-trioxa-3λs-phosphahept-l-yl cyclopentanecarboxylate(Compound 91); bis{[(t-butoxycarbonyl)oxy]methyl} {[l-({2-amino-[6-(4- methoxyphenyl)sulfanyl]-9-r-f-purin-9- yl}methyl)cycloρropyl3oxy}methylphosphonate(Compound 92); bis{[(t-butoxycarbonyl)oxy3methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]- 9-V-purin-9-yl} methyl)cyclopropyl3oxy} methylρhosphonate(Compound 93); {[1 -({2-amino-[6-(4-nitrophenyl)sulfanyl]-9-f-'-pur-n-9- yl}methyl)cycloρropyl3oxy}methylphosphonic acid(Compound 95); { [ 1 -({2-ammo-[6-(4-methoxyphenyl)sulfanyl3-9/-'-ρurin-9.- yl}methyl)cycloρropyl3oxy}methylphosphonic acid(Compound 96); ({l-[(2-amino-6-hydroxy-9-?iι'-purin-9-yl)methyl3-2-methylcyclopropyl}oxy) methylphosphonic acid(Compound 97); ({l-[(2-amino-9-rϋ,-purin-9-yl)methyl3-2-methy3cyc]opropyl}oxy)methylphosphonic acid(Compound 98); {[l-({2-amino-[6-(4-methoxyphenyl)sulfanyl3-9^ιr-purin-9-yl}methyl)-2-methyl cyclopropyljoxyjmethylphosphonic acid(Compound 99); {[l-({2-amino-[6-(4-nitrophenyl)sulfanyl3-9H-purin-9-yl}methyl)-2-methylcyclo- proρyl}oxy} methylphosphonic acid(Compound 100); {[l-({2-amino-[6-(4-methylρhenyl)sulfanyl3-9J9-purin-9-yl}methyl)-2-methyl cyclopropyljoxyjmethylphosphonic acid(Compound 101); ({l-[(2,6-diamino-9-?J-purin-9-yl)methyl3-2-methylcyclopropyl}oxy)methyl phosphonic acid(Gompound 102); ({1 -[(6-amino-9-r7-purin-9-yl)methyl3-2-methy yclopropyl} oxy)methylphosphonic acid(Compound 103); 3-[({l-[(2-amino-6-hydroxy-9-r-r-purin-9-yl)methyl3-2-methylcyclopropyl)oxy) methyl3-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λf>phosphanon-l-yl pivalate(Compound • 105); 3-[({ 1 -[(2-amino-9-?-?'-purin-9-y])methyl]-2-methylcyclopropyl} oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 106); 3-[({l-[(6-amino-9-fy-purin-9-yl)methyl3-2-methylcyclopropyl}oxy)methyl3-8,8- dimεthyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 107); 3-({[l-({2---mino-6-[(4-methoxyphenyl)sulfanyl3-9-r7-purin-9-yl}methyl)-2- methylcyclopropyl3oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ3-phosphanon-l-yl pivalate (Compound 108); bis{[(isopropoxycarbonyl)oxy3methyl}[(l-{[2-am o-6-hydroxy-9-r-^purin-9-yl] methyl} -2-methylcyclopropyl)oxy]methylphosphonate(Compound 109); bis { [(i sopropoxycarbonyl)oxy]methyl} ({ 1 -t(2------mo-9J-f-purin-9-yl)methyl]-2- methylcyclopropyI}oxy)methylphosphonate(Compound 110); bis{[(isopropoxycarbonyl)oxy3methyl} {[l-({2---mino-[6-(4-methoxyphenyl) sulfanyI3-9-?7-purin-9-yl}methyl)-2-methylcyclopropyl3oxy}methylphosphonate (Compound 112); bis { [(t-butoxycarbonyl)oxy3methyl} { [1 -({2-amino-[6-(4- methoxyphenyl)sulfanyl3-9it"-purin-9-yl}methyl)-2- methylcyclopropyljoxy} methylphosphonate(Compound 113); bis(2,2,2-trifluoroethyI){[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl3-9H-purin-9- yl}methyl)-2-methylcyclopropyl3oxy}methylphosphonate(Compound 114); bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4---itrophenyl)sulfanyl3-9^'-purin-9-yl} methyl)-2-methylcyclopropyl3 oxy}methylphosphonate(Compound 115); bis{[(t-butoxycarbonyl)oxy3methyl} {[1 -({2-amino-[6-(4-nitrophenyl)sulfanyl3- 9-?J-purin-9-yl} methyl)-2-methylcyclopropyl3oxy}methylphosρhonate(Compound 116); bis{ [(isopropoxycarbonyl)oxy3methyl} {[1 -({2-amino-[6-(4-nitropbenyl)sulfanyl]- 9-f7-purin-9-yl} methy3)-2-methylcyclopropyl3oxy}methylphosphonate(Compound 117); 3-({[l-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9--?-purin-9-yl}methyl)-2-methyl cycloproρyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 118); ({ 1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methy-3cycIopropyl} amino)methyl phosphonic acid(Compound 119); ({l-[(2-amino-9£'-purin-9-yl)methyl3cyclopropyl}amino)methylphosphonic acid(Gompound 120); ({l-[(6---mino-9- -purin-9-yI)methyl3cyclopropyI}amino)methylphosphonic acid(C6mpound 121); [{l-[(2---mino-6-hydroxy-9--7-purin-9-yl)methyl3(^clopropyl}(me l)amino] methylphosphonic acid(Compound 122); [{l-[(6---mino-9 r'-purin-9-yl)methylJcyclopropyl}(ethyl)amino3methylphospho--Jc acid(Compound 125); 3-{[{(l-[(6---mmo-9--7-purin-9-yl)n-ethyl3cyclopropyl)(methyl)amino)methyl)-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 126); bis{[(isopropoxycarbonyl)oxy3methyl}[{l-[(6-an-ino-9*rϊ-purin-9-yl)methyl3cyclo propyl} (methyl)amino]methylphosphonate(Compound 127); 3-{[{l-[(2-amino-9-9'-ρurin-9-yl)methyl3cyclopropyl}(ethyl)amino3methyl}-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 129); (E)-2- { 1 -[(2-aπ-ino-6-hydroxy-9i/-purin-9-yl)methyl3cyclopropyl} ethenyl phosphonic acid(Compound 130); . (E)-2- { 1 -[(2-amino-9--7-purin-9-yl)methyl3cyclopropyl} ethenylphosphonic acid (Compound 131); (E)-2-{l-[(6-amino-9--7-purin-9-yl)methyl3cyclopropyl} ethenylphosphonic acid (Compound 132); 3-((E)-2-{l-[(2-amino-6-hydroxy-9-y-purin-9-yl)methyl3cyclopropyl}ethenyl)-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l -yl piva!ate(Compound 133); 3-((--- -2-{l-[(6---π-ino-9--y-ρurin-9-yl)methyl3cyclopropyl}ethenyI)-8,8-dimethyl- 3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 134); (E)-2-{l-[(6-amino-9-ζt"-purin-9-yl)methyl3cyclopropyl}-l-propenylphosphonic acid(Compound 137); 2-{l-[(2-amino-6-hydroxy-9if"-purin-9-yl)methyl3cyclopropyl}ethylphosphonic acid(Compound 138); 2-{ 1 -[(2---mmo-9#-purin-9-yl)methyl]cyclopropyl}ethylphosphonic acid
(Compound 139); 2-{ 1 -[(6-amino-9#-purin-9-yl)methyl3cyclopropyl} ethylphosphonic_acid (Compound 140); . 2-[l-({2-an-ino-6-[(4-methylphenyl)suIfanyl3-9H-ρurin-9-yl}methyl)cyclopropyl] ethylphosphonic acid(Compound 141); 2-{l-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl3cyclopropyl}propylphosphonic acid(Compound 142); 2- { 1 -[(6-amino-9-9-purih-9-yl)methyl] cyclopropyl} propylphosphonic acid (Compound 143); 2-{l-[(2-aminQ-9i-f-purin-9-yl)methyl]cycloproρyl}propylphosphor-ic acid (Compound 144); 3-(2-{ l-[(6-amino-9--_r-puτin-9-yl)methyl]cyclopropyl}propyl)-8,8-d-methyl-3,7- dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 145); ({l-[(2-amino-6-hydroxy-9-?--purb-9-yl)methyl3-2,2-dimethylcyclopropyl}oxy) methylphosphonic acid(Compound 146); ({l.[(2-a---ino-9---r-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl phosphonic acid(Comppund 147); ({ 1 -[(6-amino-9Jϊ-purin-9-yl)methyl]-2,2-dimethylcyclopropyl} oxy)methyl phosphonic acid(Compound 148); 3-[({ 1 -[(2-amino-6-hydroxy-9JE-r-purin-9-yl)methyl]-2,2- dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ -phosphanon-l- yl pivalate(Compound 149); 3-[({l-[(2-amino-9-?7-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl3- 8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phΘsphanon-l-yl pivalate(Compound 150); 3-[({l-[(6-amino-9i-'-purin-9-yl)methyl3-2,2-d-methylcyclopropyl}oxy)methyl3- 8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 151); bis{[(isopropoxycarbonyl)oxy3methyl}({ l-[(6---mino-9H-purin-9-yl)methyl3-2,2- dimethylcyclopropyl}oxy)methylphosphonate(Compound 152); and bis{[(isopropoxycarbonyl)oxy]methyl}[(l-{[2---mino-6-hydroxy-9---T-purin-9-yl] methyl } -2,2-dimethylcyclopropyl)oxy3methylphosphonate(Compound 153). The compound of formula (1) according to the present invention can be prepared by a process as explained below, and thus, it is another object of the present mvention to provide such a preparation process. However, conditions of the process, such as for example, reactants, solvents, bases, amounts of the reactants used, etc. are not restricted to those explained below. The compound of the present invention may also be conveniently prepared by optionally combining the various synthetic ways described in the present specification or known in the arts, and such a combination can be easily performed by one of ordinary skill in the art to which the present invention pertains.
The compound of formula (1) of the present invention can be prepared characterized in that (a) a compound represented by the following formula (2):
in which R1, R2, R3, R4, R5, R7, RB and Y are defined as previously described, and L represents a leaving group, preferably methanesulfonyloxy, p-toluenesulfonyloxy or halogen, is reacted with a compound represented by the following formula (3):
QH (3) in which Q is defined as previously described, to produce the compound of formula (1), (b) a compound represented by the following formula (9):
in which R1, R2, R3, R7, R8, Y and L are defined as previously described, and R9 and R10 independently of one another represent optionally substituted alkyl, is reacted with the compound of formula (3) to produce a compound represented by the following formula (10):
in which R1, Rz, R3, R7, R8, Y, Q, Rs and R10 are defined as previously described, and the resulting compound of formula (10) is hydrolyzed in the presence of a Lewis acid to produce a compound represented by the following formula (la):
in which R1, R2, R3, R7, R8, Y and Q are defined as previously described, or
(c) groups R4' and R5* are introduced into the compound of formula (la) to produce ' a compound represented by the following formula (lb):
in which R1, R2, R3, R7, R8, Y and Q are defined as previously described, and R4' and R5" represent R4 and Rs with the exception of hydrogen, respectively, or further the compounds thus obtained are subjected to conventional conversions (see: USP 6,037,335, 5,935,946, and 5,792,756).
In the above process variants (a) to (c) for preparing the compound of formula (1), the reactions may be carried out in a solvent and in the presence of a base. As the solvent, one or more selected from a group consisting of dimethylformamide, dichloromethane, tetrahydrofuran, chloroform, l-methyl-2-pyrrolidinone and dimethylacetamide can. be mentioned, and as the base one or more selected from a group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogen bis(trimethylsilyl)amide, sodium amide, cesium carbonate and potassium bis(trimethylsilyl)amide can be mentioned. The Lewis acid which can be used in the process variant (b) includes trimethylsilylhalide. Further, in the process variant (c) for introducing the groups R4' and R5'into the compound of formula (la), this compound is subjected to an ether-forming reaction with an alkylhalide in the presence of a base, or is treated with tb'onyl chloride, oxalyl chloride or phosphorus pentachloride to produce a dichlorophosphonate derivative which is then reacted with a • suitable alcohol or amine to give the desired compound.
The phosphonate compound of formula (2) used as a starting material in the above process is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (2).
The compound of formula (2) wherein Y is 0, R1 is hydrogen, and each of R2, R3, R7 and R s hydrogen or alkyl, that is, a compound of the following formula (8), can be prepared characterized in that ( i ) an ethylglycolate, the alcohol group of which is protected, represented by the following formula (4):
in which P1 represents an alcohol-protecting group, preferably benzyl(Bn), tetrahydropyranyl(THP), t-butyldiphenylsilyl(TBDPS), or t-butyldimethylsilyl(TBDMS), is reacted with ethyl magnesium bromide[C2HjMgBr3 or the corresponding alkyl magnesium bromide or alkyl magnesium chloride in the presence of titanium tetraisopropoxide[Ti(OiPr)4], ( ii) the resulting cyclopropanol represented by the following formula (5):
in which P1 is defined as previously described and each of R2', R3', Rτ and R8' represents hydrogen or alkyl, is subjected to an ether-forming reaction in the presence of a base with a compound represented by the following formula (6):
in which L, R4 and R5 are defined as previously described, to produce a phosphonate compound represented by the following formula (7):
in which P\ R2", R3', R71, R8*, R4 and R5 are defined as previously described, and (iii) the alcohol-protecting group of the resulting compound of formula (7) is removed and a leaving group(L) is introduced to produce a compound represented by the following formula (8):
in which L, R2', R3', Rτ, Rr, R"and R5are defined as previously described.
The process for preparing the simplest compound of formula (8) (that is, all of R2', R3', Rτ and R8'are hydrogen) is briefly depicted in the following Reaction Scheme 1 :
Reaction Scheme 1
The specific reaction conditions of the above process can be referred to the following Preparations and Examples.
Further, the compound of formula (2) wherein Y is -CH,-, and each of R1, R2, Rs, R7 and R8is hydrogen, that is a compound of the following formula (11):
in which L, R4and R5 are defined as previously described, can be prepared by a process as depictd in the following Reaction Scheme 2:
Reaction Scheme 2
Reaction Scheme 2 is briefly explained below. ( i ) According to a known method (see: JOC, 1975, Vol.40, 2969-2970), dialkylmalonate is reacted with dihaloethane to give malonic acid wherein cyclopropyl group is introduced into its 2-position. (ii) The malonic acid is reduced to give diol compound, one hydroxy group of which is then protected with a suitable protecting group (P'is defined as previously described). Then, the other hydroxy group is oxidized to an aldehyde group, (iii) The resulting aldehyde compound is reacted with tetraalkylmethylenediphosphonate to give the desired phosphonate compound, (iv) The phosphonate compound thus obtained is reduced to give a compound having no unsaturated bond, alcohol-protecting group (P1) is removed, and a leaving group (L) is introduced to give the compound of formula (11).
Further, the compound of formula (2) wherein Y is -N(CH3)- and each of R1, R2, R3,R7 and R8is hydrogen, that is a compound of the following formula (12):
in which L, R4 and Rs are defined as previously described, can be prepared by a process as depictd in the following Reaction Scheme 3:
Reaction Scheme 3
(-2) Reaction Scheme 3 is briefly explained below. ( i ) Diethyl 1,1-cyclopropyl dicarboxylate is selectively hydrolyzed to give a monocarboxylic acid, .(ii) An amine group is introduced into the monocarboxylic acid according to the known Curtious Reaction (see: S. Linke, G. T. Tisue and W. Lowows-d, J. Am. Chem. Soc. 1967, 89, 6308). (iii) The amine group is protected with a suitable protecting group [P2 may be carbamate . or various benzyl protecting groups, or alkyl group (methyl, ethyl, etc.)3. (jv) The opposite ester group is reduced into a hydroxy group, which is then protected (P1 is defined as previously described), (v) The compound protected with protecting groups is reacted with methyl iodide in the presence of sodium hydride to introduce methyl group into the amine group, (vi) The amine-protectϊng group is removed and the resulting compound is reacted with dialkylbromomethylphosphonate to give the desired phosphonate compound, (vii) The alcohol-protecting group (P1) is removed from the phosphonate compound thus obtained and then a leaving group (L) is introduced to give the compound of formula (12).
The specific reaction conditions of the above processes can be referred to the following ---reparations and Examples.
After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for example, chromatography, recrystallization, etc. ' The compound of formula (1) of the present invention can be effectively used as an antiviral agent. Therefore, it is another object of the present invention to provide a composition for the treatment of viral diseases, which comprises as an active ingredient the compound of formula (1), pharmaceutically acceptable salt, hydrate, solvate or isomer thereof together with the pharmaceutically acceptable carrier.
When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging generally from 0.1 to lOOOOmg, preferably from 0.5 to lOOmg per kg of body weight a day. The total daily dosage may be administered in once or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex or hygienic condition of the subject patient, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc. The compound of the present invention may be administered in the form of injections or oral preparations. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include water, Ringer's fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic, acid may also be used for injections.
• As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent.
When the compound according to the present invention is clinically applied for obtaining the desired antiviral effect,- the active compound of formula (1) can be administered in combination with one or more substances selected from the known anti- cancer or antiviral agents.
However, preparations comprising the compound of the present invention are not restricted to those explained above, but may contain any substances useful for the treatment or prevention of cancers or viral diseases. The following Preparations (1-35) and Examples (1-52) are disclosed by Choi et al. in International Publication No. WO 02/057288, pgs. 38-82, and are explicitly incorporated herein:
Preparation 1 Synthesis of l-({|t-butyl(diphenyl)silyl3oxy}methyl)cyclopropanol According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 12g(35 mmole) of ethyl 2-{[t- butyl(diphenyl)silyl3oxy} acetate was dissolved in 200ml of tefr--hyhof ran(THF) and 2.2 m£ of titam'umtetraisopropoxide was added thereto. To the mixture was slowly added 29.2m6 of ethylmagnesiumbromide(3.0M in THF), and the reaction solution was stirred for 12 hours at room temperature. 20-nt of saturated ammonium chloride was added to stop the reaction. About 150m of tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 200ιrΛ of ethyl acetate. The ethyl acetate extract was distilled under reduced pressure to give 13.4g(Yield 100%) of the title compound as a white solid.
'H NMR(CDC13) δ 0.44 (q, 2H), 0.78 (q, 2H), 1.09 (s, 9H), 3.67 (s, 2H), 7.41 (m, 6H), 7.70(m, 4H) ESI: 344 (M+NH , C20H26O2Si
Preparation 2 Synthesis of diisopropyl {[l-({[t-bu-yl(dipheny-)s--yl]oxy}methy-)cyclopropyl] oxy} methylpbosphonate
The compound prepared in Preparation 1 (6.5g) was dissolved in 10mt of dimethylformamide(DMF), 32mA of lithium t-butoxide(1.0M in THF) was added thereto, and the resulting mixture was stirred for 10 minutes. To the mixture was added 7.0g of diisopropyl bro omethylphosphonate, and then the temperature was raised to 40 U and the mixture was stirred for 4 hours. Dimethylforrnamide(DMF) was removed by distillation under reduced pressure, 40m£ of saturated ammonium chloride was added to the residue, which was then extracted with ethyl acetate. The ethyl acetate extract was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate n-hexane=l/l, v/v) to give 6.8g(Yield 70%) of the title compound.
Η NMR(CDC13) δ 0.53 (m, 2H), 0.88 ( , 2H), 1.07 (s, 9H), 1.29 (t, 12H), 3.78 (s, 2H). 3.98 (d, 6H), 4.75 ( , 2H), 7.40(m, 6H), 7.67(m, 4H) Preparation 3. Synthesis of diisopropyl{l-[(hydroxymetby-)cyclopropyl]oxy}methyl phosphonate
The compound prepared in Preparation 2 (8.3g) was dissolved in lOOnA of methanol, 3.1g of ammonium fluoride was added thereto, and the resulting mixture was heated under reflux for 2 hours. After the reaction was completed, methanol was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eIuent: dichJoromethane/methanol=20/l, v/v) to give 3.6g(Yield 82%) of the title compound.
Η MR(CDC13) δ ' 0.60 (t, 2H), 0.87 (t, 2H), 1.28 (d, 12H), 2.5 (br s, IH), 3.65 (s, 2H), 3.83 (d, 2 H), 4.82 (m, 2H) ESI: 267 (M+l)+, Cl 1H2304P Preparation 4 Synthesis of {l-[(diisopropoxyphosphoryl)methoxy]cyclopropyl} methyl methane- sulfonate
The compound prepared in Preparation 3 (1.5g) was dissolved in 50π-H of dicHoromethane, 0.85-αt of triethylamine and 0.84g of methanesulfonylchlonde were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate/n-hexane=l/l, v/v) to give 1.63g(Yield 81%) of the title compound.
Η NMR(CDC13) δ 0.77 ( , 2H), 1.09 (m, 2H), 1.32 (m, 12H), 3.10 (s, 3H), 3.82 (m, 2H), 4.33 (s, 2H), 4.71 (m, 2H)
Preparation 5 Synthesis of diisopropyl({l-|(6-amino-9J-T-purin-9-yl)methyl3cyclopropyl}oxy) methylphosphonate
The compound prepared in Preparation 4 (430mg) was dissolved in 18mA of dimethylformamide, 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto, and the resulting mixture was heated under reflux over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl • " acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatography(eluent: dichloromethane methanol=20/l, v/v) to give 201mg(Yield 44%) of the title compound. ΗN-vflKCDCla) δ 0.86 (t, 2H), 1.01 (t, 2H), 1.24 (d, 613), 1.34 (d, 6H), 3.86 (d, 2H), 4.34 (s, 2H), 4.71 (m, 2H), 5.97 (br s, 2H), 8.32 (s, IH), 8.58 (s, IH) ESI: 384 (M+l)4, C16H25N504P
Preparation 6 Synthesis of diisopropyl({l-[(2-amino-6-chloro-9-fir-purin-9-yI)methyrj cyclopropyl} oxy)methylphosphonate
The compound prepared in Preparation 4 (1.6 g) was dissolved in 70mfc of dimethylformamide, 2 9mg(60% purity) of sodium hydride and 773 mg of 2-amino-6- ch3oro-9 -purine were added thereto, and the resulting mixture was stirred for 4 hours while heating at a temperature of up to 801.. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate, and the ethyl acetate extract was distilled under reduced pressure. The residue was purified by silica gel column chromatogra'phy(e]uent: dichloromethane/methanol=20/l, v/v) to give 765mg(Yield 40%) of the title compound.
!H MR(CDC13) δ 0.80 (t, 2H), 1.02 (t, 2H), 1.27 (d, 6H), 1.28 (d, 6H), 3.82 (d, 2H), 4.21 (s, 2H), 4.68 (m, 2H), 5.13 (br s, 2H), 8.15 (s, IH) ESI: 418 (M+l)+, C16H25C1N504P
Preparation 7 Synthesis of diisopropyl[(l {[5-methyl-2,4-dioxo-3,4-dihydro-l(2H pyrimidiny-3roethy-} cyclopropyl)o--yjmethylphosphonate
The compound prepared in Preparation 4 (118mg) and thymine were reacted • according to the same procedure as Preparation 6 to give 26mg(Yield 21%) of the title compound.
ΗNMR(CDC13) δ 0.82 (t, 2H), 0.95 (t, 2H), 1.31 (m, 12H), 1.92 (s, 3H), 3.74 (d, 2H), 3.89 (s, 2H), 4.71 (m, 2H), 7.62 (s, IH), 9.15 (s, IH) ESI: 375 (M+l)+, C16H27N206P
Preparation 8 Synthesis of l-({[t-bu-yI(diphe-ιyl)siIyIJoxy}methyl)-2-methylcyc]opropanol
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 50g(146 m ole) of ethyl 2-{[t- butyl(diphenyl)silyl]oxy} acetate was dissolved in 700mA of tetrahydrofuran(THF) and 30.0mA of titaniu tetraisopropoxide was added thereto. To the mixture was slowly added 290mA of propylmagnesiumcJ-loride(2.0M in THF) at -10*C, and the reaction solution was stirred for 12 hours at room temperature. 200mA of saturated ammonium chloride was added to stop the reaction. The tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 2000mA of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42g of the title compound.
ΗNMR(CDC13) 6 0.06 (t, IH), 0.88 (dd, 2H), 0.97 (d, 3H), 1.09 (s, 9H) 1.1 (m, IH), 2.78 (s, IH), 3.70 (d, IH), 3.86 (d, IH), 7.41 (m, 6H), 7.70 (m, 4H) ESI: 363 (M+Na)*, C21H2802Si
Preparation 9 Synthesis of diisopropyl {[l-({lt-butyl(diphenyl)silyl]oxy}methyI)-2--nethyl cyclopropyl}oxy}methylphosphonate
The compound prepared in Preparation 8 (4.2g) was reacted according to the same procedure as Preparation 2 to give 3.3g of the title compound.
'H NMR(CDC13) δ 0.04 (t, IH), 0.96 (dd, IH), 0.97 (d, 3H), 1.05 (m, IH), 1.06 (s, 9H), 1.23 (t, 12H), 3.72 (d, IH), 3.95 (d, 2H), 3.98 (d, IH), 4.75 (m, 2H), 7.40 (m, 6H), 7.68 (m, 4H) Preparation 10 Synthesis of diisopropyl{l-[(hydroxymethyl)-2-methylcycIopropyl]o--y} methylphosphonate
The compound prepared in Preparation 9 (3.3g) was reacted according to the same procedure as Preparation 3 to give 1.7g of the title compound.
Η NMR(CDC13) δ 0.03 (t, IH), 0.95 (dd, IH), 0.96 (m, IH), 1.11 (d, 3H), 1.35 (d, 12H), 2.17 (br s, IH), 3.80 (d, 2H), 3.96 (d, IH), 4.80 (m, 2H) ESI: 303 <M+Na)+, C12H22504
Preparation 11 Synthesis of diisopropyl({l-[(6-a-nino-9-rT-purin-9-yl)methyl]-2-methyl cyclopropyl} oxy)methylphosphonate
The compound prepared in Preparation 10 (1.5g) was dissolved in 50ml of dichloromethane, 0.85mA of triethylamine and 0.84g of methanesulfonylchloride were added thereto, and the resulting mixture was stirred for 30 minutes at room temperature. Saturated ammonium chloride was added to stop the reaction. The product was extracted with dichloromethane .and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was used in the next reaction without any purification. 'H NMR(CDC13) δ 0.42 (m. IH), 1.12 (d, 3H), 1.25 (m, IH), 1.32 (m, 12H), 1.33 (m, IH), 3.10 (s, 3H), 3.76 (m, 2H), 4.31 (d, IH), 4.71 (d, IH), 4.76 ( , 2H)
The ethanesulfonate thus obtained (430mg) was dissolved in 18mA of dimethylformamide, and 57.6mg (60% purity) of sodium hydride and 162mg of adenine were added thereto. The reaction mixture was refluxed under heating over 4 hours. Saturated ammonium chloride was added to stop the reaction. The product was extracted with ethyl acetate and the ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 201mg(Yield 44%) of the title compound.
Η MR(CDC13) δ 0.53 (t, H), 1.13 (d, 3H), 1.15 (m, IH), 1.30 (m, 12H), 1.41 (m, IH), 1.85 (brs, 2H), 3.81 (m, 2H), 4.43 (m, 2H), 4.70 (m, 2H), 5.65 (br s, 2H), 8.26 (s, IH), 8.34 (s, IH) ESI: 398 (M+l)+, C17H28N504P
Preparation 12 Synthesis of diisopropy]({l-[(2-aroino-6-chIoro-9-f-r-purin-9-y-)methyl]-2- methylcyclopropyl}oxy)methylphosphonate
The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that 6-chloroguanine (2-amino-6-chloro-9-r-f-pur-ne) was used instead of adenine to give the title compound.
'H NMR(CDC13) δ 0.47 (t, J=6.4Hz, IH), 1.12 (m, 4H), 1.24 (dd, J= 2.8Hz, 6.4Hz, 6H), 1.28 (t, J=6.0Hz, 6H), 1.38 (m, IH), 3.80 (m, 2H), 4.28 (m, 2H), 4.68 (m, 2H), ' 5.13 (brs, 2H), 8.15 (s, IH) ESI: 432 (M+l)+, C17H27C1N5O4P
Preparation 13 Synthesis of diisopropyl[(l{[5-roethyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyl]methyl}-2-methylcyclopropyl)oxy3methyIphosphonate
The compound prepared in Preparation 10 was reacted according to the same procedure as Preparation 11 except that thymine was used instead of adenine to give the title compound.
Η NMR(CDC13) δ 0.48 (t, IH), 1.10 ( , 4H), 1.24 (dd, 6H), 1.28 (t, J= 6H), 1.38 (m, IH), 1.92 (s, 3H), 3.80 (m, 2H), 4.28 (m, 2H), 4.68 ( , 2H), 7.62 (s, IH), 9.15 (s, IH) ESI: 389 (M+1)4,C17H29N206P
Preparation 14 Synthesis of l-(ethoxycarbonyl)cyclopropanecarboxylic acid r™ Diethyl 1,1-cyclopropane dicarboxylate (20g) was hydrolyzed in IN NaOH (107 mA) and ethanol (220mA) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by IN HCI. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94%.
ΗNMR(CDC13) 6 1.06 (t, 3H), 1.53 (m, 2H), 1.62 (m, 2H), 4.21 (q, 2H) ESI: 159 (M+1)+C7H10O4
Preparation 15 Synthesis of ethyl l-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylate
^0^γ° O
The carboxylic acid prepared in Preparation 14 (16g) was dissolved in dichloromethane, 10.8mA of oxalyl chloride was added dropwise, and 2 drops of dimethylformamide was added. The reaction mixture was stirred at room temperature for 3- hours and distilled under reduced pressure to give ethoxycarbonyl 1,1-cyclopropane carbonylchloride. This compound, not purified, was dissolved in 30mA of dimethylformamide and the resulting solution was cooled with water-ice. 36g of N--N3 was added and the reaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 300mA of water and 200mA of diethylether, and the diethylether extract was concentrated to give crude compound which was purified by silica gel column to give an azide compound.
Η NMR(CDC13) δ 1.28 (t, 3H), 1.54 ( , 4H), 4.19 (q, 2H)
To the azide compound thus obtained (13g) was added dropwise 11mA of benzyl alcohol and the reaction mixture was heated to 100'C, by which the reactants were vigorously reacted with each other with the generation of gas. The reaction mixture was heated at 100°C for further 1 hour, cooled to room temperature, and distilled under reduced pressure to remove benzyl alcohol. The residue was purified by silica gel column to give the title compound. Η NMR(CDC13) δ 1.19 (m, 5H), 1.54 (m, 2H), 4.11 (m, 2H), 5.15 (br.s, 2H), 7.32 (m, 5H)
Preparation 16 Synthesis of benzyl l-{[t-butyl(diphenylsily-)oxy]met--ylcyclopropy-} (methyl)carbamate
The carboxylate prepared in Preparation 15 (13.2g) was dissolved in diethylether, to which 1.3g of L1BH4 dissolved in diethylether was slowly added dropwise. The reaction misture was stirred at room temperature for 16 hours, and 50mA of methanol and 5 mA of IN HCI were added dropwise thereto. The reaction mixture was stirred for 2 hours, the precipitate was removed by suction filtration, and the solvent in the filtrate was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl l-(hydroxymethyl)cyclopropylcarbamate.
This compound (9.3g) was dissolved in dichloromethane, and 4.2g of imid-izole and 33.5mA of t-butyld-phenylsilylchJoride were added in order. The reaction mixture was stirred at room temperature for 4 hours- nd the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give benzyl 1- ({[t-butyl(diphenyl)silyl3oxy}methyl)cyc3opropylcarbamate.
ΗNMR(CDC]3) δ 0.71-1.19 ( , AH), 3.04 (s, 9H), 3.68 (br.s, 2H), 5.04 (s, 2H), 7.25-7.45 (m, 3 IH), 7.62 (d, 4H) The carba ate thus obtained (5.5g) was dissolved in THF, 3.5mA of methane iodide (Mel) was added dropwise and then Ig of NaH was added. The reaction mixture was stirred at room temperature for 4 hours and then extracted with 100mA of diethylether and 100mA of water. The diethylether extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound. Η NM-KCDCI3) δ 0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H), 3.55- 3.80 (m, 2H), 5.10 (s, 2H), 7.24-7.45 (m, 11H), 7.61 (m, 4H)
Preparation 17 Synthesis of diisopropyl[l-({[t-butyl(dipheny-)sϋyl]oxy}methyl)cyclopropyl) (methyl)amino]methyIpbosphonate
The carbamate prepared in Preparation 16 (l.Og) was dissolved in ethanol, lOOmg of 10% Pd/C was added, and the reaction mixture was subjected to a hydrogenation under hydrogen atmosphere. • After the reaction was completed, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give l-({[t-butyl(diphenyl)silyl3oxy}methyl)-N-methyIcycIopropaneamine.
Η NMR(CDC13) δ 0.36 (m, 2H), 0.65 (m, 2H), 1.05 (s, 9H), 2.36 (s, 3H), 3.57 (s, 2H), 7.37-7.45 (m, 1 H), 7.66 (d, 4H)
The methylcyclopropaneamine thus obtained (l.Og) was dissolved in dichloromethane, to which 1.03 mA of diisopropylethylamine and 1.3 mA of (diisopropyl ρhosphoryl)methyl trifluoromethansulfonate were added dropwise. The reaction mixture was reacted under stirring at room temperature for 4 hours, and then extracted with 100mA of diethylether and 300mA of water. The solvent in the diethylether extract was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound. Η NMR(CDC13) δ 0.42 ( , 2H), 0.69 (m, 2H), 1.04 (s, 9H), 3.25 (d, 6H), 1.30
(d; 6H)S 2.62 (s, 3H), 3.25 (d, 2H), 3.64 (s, 2H), 4.68 (m, 2H), 7.39 (m, 6H), 7.65 (d, 4H) Preparation 18 Synthesis of diisopropyl(l-{[(6-amino-9--ϊ-purin-9-y-)met--yl]cycIopropyl} (methyl)amino)methylphosphonate
The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 U for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methyla inediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
'H N-V-R(CDC13) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s,- 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 5 to give the title compound.
Η N-vlR(CDCl3) δ 0.78 (m, 2H), 0.86 (m, 2H), 1.25 (m, 12H), 2.35 (s, 3H), 4.10 (s, 2H), 4.68 (m, 2H), 5.33 (m, 2H), 8.32 (s, IH), 8.58 (s, IH) ESI: 397 (M+l)+, C17H29N603P
Preparation 19 Synthesis of diisopropyl(l-{[(2-amino-6-chloro-9-r-r-purin-9-yl)methyl] cyclopropyl}(methyl)amino)methylphospbonate
The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and
1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 "C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give ethylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.
'H NMR(CDC13) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s, 3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 ( , 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 6 to give the title compound. 'HNMR(400MH--, CD3OD): δ 0.79 (m, 2H), 0.89 (m, 2H), 1.26 (m, 12H), 2.38 (s, 3H), 2.76 (d, 2H, J=7Hz), 4.11 (s, 2H), 4.65 (m, 2H), 5.13 (m, 2H), 8.02 (s, IH) ESI: 431(M+1)+, C17H28C1N6O3P
Preparation 20 Synthesis of diisopropyl[(l-{[5-methyI-2s4-dioxo-3,4-dihydro^L(2H)- pyri-nidinyrjmethyl}cyclopropyl)(methyl)amino]methylphosphonate
The compound prepared in Preparation 17 (0.32g) was dissolved in methanol and 1.5g of ammonium fluoride was added dropwise. The reaction mixture was reacted under stirring at 60 U for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column to give methylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol. Η NMR(CDC13) δ 0.56 (m, 2H), 0.73 ( , 2H), 1.31 (m, 12H), 2.56 (s, 3H),
3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)
The compound thus obtained was consecutively reacted according to the same procedure as Preparations 4 and 7 to give the title compound.
'H NMR(CDC13) δ 0.79 (m, 2H), 0.90 ( , 2H), 1.31 (m, 12H), 1.92 (s, 3H), 2.38 (s, 3H), 3.75 (d, 2H), 4.10 (s, 2H), 4.65 ( , 2H), 7.62 (s, IH), 9.15 (s, IH) Preparation 21 Synthesis of 1,1-cycIopropanedicarboxylic acid
i 50% NaOH 187mA was dissolved 15g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise cone, sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give 6.2g of the title compound as a white solid.
ΗNMR CDCla) δ 1.88 (s, 4H)
Preparation 22 Synthesis of [l-({[t-butyl(dipheny-)s0y-]o--y}methyI)cyc-opropy-3-netbanol
Lithium aluminum hydride (LAH) 15.3g was dissolved in 39g of tetrahydrofuran, and 11.7g of the carboxylic acid prepared in Preparation 21 was slowly added dropwise at OV. The reaction solution was refluxed for 17 hours. The reaction was stopped by adding 30% HCI at room temperature and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified by silica gel column to give 8.2g of diol compound.
Η NMR(CDC13) δ 0.56 (s, 4H), 2.22 (s, 2H), 3.63 (s, 4H)
The compound thus obtained (400mg) was dissolved in 12mA of THF, 184mg of NaH and 1.16g of t-buty-d-phenylsilylchloride (TBDPSC1) were added, and the resulting mixture was refluxed for 6 hours. The reaction was stopped by adding 10mA of water and the mixture was extracted with ethyl acetate, The extract was distilled under reduced pressure and the residue was purified by silica gel column to give l.lg of the title compound.
Η NMR(CDC13) δ 0.33 (t, 2H), 0.48 (t, 2H), 1.23 (s, 9H), 3.59 (d, 4H), 7.42 (m, 6H), 7.68 (no, 4H) Preparation 23 Synthesis of diethyl(E)-2-[l-({[t-butyl(diphenyI)silyl]o--y}methyl)cyclopropylJ ethenylphosphonate
The compound prepared in Preparation 22 (2g) was dissolved in 50mA of dichloromethane, and 1.03g of N-methylmorpholine N-oxide and 103mg of tetrapropylammom'umperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and the reaction was stopped by adding 20mA of water. The reaction solution was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 2.0g of aldehyde' compound.
Η NMR(CDC-3) 6 1.03 (s, 9H), 1.04 (t, 2H), 1.05 (t, 2H), 3.94 (s, 2H), 7.37 (m, 6H), 7.64 (m, 4H), 9.30 (s, 3H)
Tetraethylm ethylene diphosphonate (1.7g) was dissolved in 60mA of tetrahydrofuran (THF). At -78 U, 264mg of NaH was added, the resulting mixture was stirred for 20 minutes, and then 1.9g of the aldehyde compound as obtained above was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction was stopped by adding 20mA of water. The reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column to give 2.32g of the title compound.
ΗN R^DO,) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s, • 2H), 4.05 ( , 4H), 5.70 (m, 3H), 6.42 (m, IH), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+'C28H41O4PSi
Preparation 24 Synthesis of diethyl 2-[l-(hydroxy-nεthy-)cyclopropy-]ethenylphosphonate
The compound prepared in Preparation 23 was reacted according to the same procedure as Preparation 3 to give the title compound.
ΗNMR^DCl,) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H), 3.71 (s, 2H), 4.05 (m, 4H), 5.70 (m, IH), 6.42 (m, IH), 7.43 (m, 6H), 7.64 (d, 4H) ESI: 501 (M+l)+1 C28H4104PSi
Preparation 25 Synthesis of diethyl 2-{l-[(6-am-no-9--7-purin-9-y-)-nethyl]cyclopropyI} ethenylphosphonate
& t -o^
The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 5 to give the title compound.
]H MR(CDC13) δ 1.07 (t, 2H), 1.19 (t, 2H), 1.22 (t, 6H), 3.93 (s, 4H), 4.33 (s, 2H), 5.55 (s, 2H), 5.63 (m, IH), 6.49 (m, IH), 7.88 (s, IH), 8.37 (s, IH) ESI.-352 (M+l) ,C15H22N5O3P Preparation 26 Synthesis of diethyl 2-{l-[(2-amino-6-chloro-9-ar-purin-9-yl)methyl) cyclopropyl} ethenylphosphonate
The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 6 to give the title compound.
' !H NMR(CDC13) δ 1.06 (t, 2H), 1.15 (t, 2H), 1.23 (t, 6H), 3.93 (s, 4H), 4.18 (s, 2H), 5.12 (s, 2H), 5.59 (m, IH), 6.58 (m, IH), 7.81 (s, IH) ESI:386 (M+l)+'C15H21ClN5O3P
Preparation 27 Synthesis of diethyl 2-(l-{[5-roetbyl-2,4-dio-.o-3,4-dihydro-l(2H)-pyrimidinyI] methyl} cyclopropyl)ethenylphosphonate
The compound prepared in Preparation 24 was reacted according to the same procedure as Preparations 4 and 7 to give the title compound. Η N_V-R(CDC13) δ 0.93 (t, 2H), 1.01 (t, 2H), 1.24 (t, 6H), 1.92 (s, 3H), 3.91 (s,
2H), 3.96 ( , 4H), 5.49 (m, 3H), 5.87 (m, IH), 7.62 (s, 3H). 9.15 (s, IH) ES 343 (M+1)+-C15H23N205P
Preparation 28 Synthesis of l-({[t-butyl(diphenyI)silyI3oxy}methyl)-2,2-dimethyIcyclo- propanol
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 10g(29 mmole) of ethyl 2-{[t- butyl(diphenyl)silyl3oxy} acetate was dissolved in 100mA of tetrahydrofuran (THF) and 6.0 mA of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 37 t of isobutylmagnesiumbromide(2.0M in THF) at -10U, and the reaction solution was stirred for 12 hours at room temperature. 50mA of saturated ammonium chloride was added to stop the reaction. The tetrahydrofuran (THF) used as .a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 500 mA of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 5.0g of the title compound.
Η NMR(CDC13) δ 0.25 (d, IH), 0.51 (d, 2H)', 0.99 (s, 3H), 1.07 (s, 9H), 1.22 (s, 3H), 3.71 (d, IH), 3.91 (d, IH), 7.41 (m, 6H), 7.70 (m, 4H) ESI: 355 (M+l)+, C22H30O2Si
Preparation 29 Synthesis of diisopropyl {[l-({l--bu-yl(dipbeny-)sily-]oxy}methy-)-2,2-dimethyI cyclopropy-]oxy}n-e-hy-phosphonate
The compound prepared in Preparation 28 was reacted according to the same procedure as Preparation 2 to give the title compound. 'H NMR(CDC13) 6 0.29 (d, IH), 0.60 (d, IH), 1.06 (s, 3H), 1.09 (s, 9H), 1.27 (s,
3H), 1.30 ( , 2H), 3.75 ( , 2H), 3.92 (m, 2H), 4.72 ( , 2H), 7.41 (m, 6H), 7.67 (m, 4H) ESI: 519 (M+l)+, C28H4305PSi Preparation 30 Synthesis of diisopropyl{l-[(hydroxymethyI)-292-dimethylcyc-opropyI]oxy} methylphosphonate
The compound prepared in Preparation 29 was reacted according to the same procedure as Preparation 3 to give the title compound.
Η MR(CDC13) δ 0.39 (d, IH), 0.59 (d, IH), 1.13 (s, 3H), 1.21 (s, 3H), 1.33 (d, 10 12H), 3.76 (m, 2H), 3.86 ( , 2H), 4.76 (m, 2H) ESI: 295 (M+l)+, C13H27O4P
Preparation 31 Synthesis of diisopropy-({l-[(6-amino-9£r-purin-9-y-)methyl]-2,2-dimethy- 15 cyclopropyl}oxy)metbylphospbonate
The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 11 to give the title compound.
'20 Η NMR(500MHz, CDC13): δ 0.62 (d, J=5.9Hz, IH), 0.81 (d, J=5.9Hz, IH), 1.10 (s, 3H), 1.23 (m, 15H), 3.72 (dd, J=15.1, ll.OHz, IH), 3.85 (dd, J=15.1, 5.5Hz, IH), 4.28 (d, J=15.lHz, IH), 4.58 (d, J=35.3Hz, 3H), 4.68 (m, 2H), 5.79 (bs, 2H), 8.19 (s, IH), 8.32 (s, 3H) 25 ES1: 412 (M+1)+, C18H30N5O4P
Preparation 32 Synthesis of diisopropyl({l-[(2-amino-6-iodo-9iϊ-purin-9-yl)methyl]-2,2- dimethylcyclopropyI}oxj')-nethylphosphonate
30 The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 12 except that 6-iodoguanine was used instead of 6- chloroguanine to give the title compound.
'H NMR(500MHz, CDC13): δ 0.58 (d, J=6.4Hz, IH), 0.80 (d, J=6.4Hz, IH), 1.10 (s, 3H), 1.24 (m, 8H), 3.72 (dd, J=13.0, ll.OHz, IH), 3.88 (dd, J=13.0, 9.3Hz, IH) 4.08 (d, J=15.1Hz, IH), 4.47 (d, J=15.1Hz, IH), 4.67 (m, 2H), 5.05 (bs, IH), 8.10 (s, IH) ESI: 538 (M+l)+, Cl 8H291N504P
Preparation 33 Synthesis ■ of diisopropyl[(l{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)- pyrimidinyI]methyI}-2,2-dimethylcyclopropyl)oxy]methylphosphonate
The compound prepared in Preparation 30 was reacted according to the same procedure as Preparation 13 to give the title compound.
ΗNMR(CDCI3) δ 0.58 (d, 3H), 0.80 (d, 3H), 1.10 (s, 3H), 1.24 (dd, 6H), 1.28 (t, 6H), 1.58 (s, 3H), 1.92 (s, 3H), 3.72 (dd, IH), 3.88 (dd, IH), 4.08 (d, IH), 4.47 (d, IH), 4.67 (m, 2H), 7.62 (ss IH), 9.15 (s, IH) ESI: 403 (M+1)+'C18H31N206P
Preparation 34 Synthesis of 1 -[] -({ [t-butyl(diphenyl)silyl]o--y}methyl)cyclopropyl]-l -methyl alcohol
6g of the compound prepared in Preparation 22 was dissolved in 150mA of dichloromethane. 3.0g of N-oxide and 103mg of tetraρropyl--mmoniumperruthenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20mA of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 6.0g of aldehyde compound which went to next reaction without further purification.
5.23g of the aldehyde was dissolved in 350mA of THF. The solution was cooled to -78U and 10.3mA of methylmagnesiυmbromide (3. OM solution) was slowly added to the solution and then, stirred for 1 hour at room temperature. The reaction mixture was quenched by 0.5mA of water and 0.5mA of methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=l/8, v/v) to 3.57g of title compound.
ΗNMR(CDC13) δ 0.22-(m, IH), 0.39 (m, 2H), 0.61 (m, IH), 1.06 (s, 9H), 1.24 (d, 3H), 3.3 (d, IH), 3.47 (s, 2H), 3.9 (d, IH), 7.43 ( , 6H), 7.64 (m, 6H)
Preparation 35 Synthesis of diethyl (E)-2-l-|l-({[t-butyI(diphenyl)silyl]o--y}methyl)cyclopropyl]- 1- propenylphospbonate
4g of the compound prepared in preparation 34 was dissolved in 10mA of dichloromethane. 2.1g of n-morpholine N-oxide and 209mg of tetrapropylammoniurnperrutbenate (TPAP) were added thereto at room temperature. The reaction mixture was stirred for about 1 hour at room temperature and quenched by adding 20mA of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to give 4.0g of compound which went to next reaction without further purification. Tetraethylmethylene diphosphonate (2.7g) was dissolved in 30mA of tetrahydrofuran (THF) at -78 and 4mA of n-butyllithium was added. The resulting mixture was stirred for 20 minutes, and then 1.0 g of the ketone compound as obtained above was added. The reaction mixture was stirred at room temperature for 1 hour and was stopped by adding 20mA of water. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column to give 654mg of the title compound.
Η NMR(CDC13) δ 0.58 (m, IH), 0.69 (in, 2H), 1.02 (s, 9H), 1.20 (t, 6H), 2.09 (d, 3H), 3.59 (s, 2H), 4.05 (m, 4H), 5.61 (d, IH), 7.38 (m, 6H), 7.63 (d, 4H)
Example 1 Synthesis of ({l-[(6-amino-9-r-T-purin-9-yl)πιethyl]cycIopropyl}o--y)πιethyl phosphonic acid (Compound 1) • The compound prepared in Preparation 5 (159mg) was dissolved in 15mA of dichloromethane, 1.27g of trimethylsilylbromide was added thereto, and the resulting mixture was heated under reflux for 18 hours. After the completion of reaction, the reaction mixture was extracted with water, and the water extract was distilled under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) to give 0.89g(Yield 90%) of the title compound as a white powder.
'H NMR(MeOH-d4) δ 1.02 (d, 4H), 3.95 (d, 2H), 4.55 (s, 2H), 8.40 (s, IH), 8.55 (s, IH) ESI: 300 (M+l)+, Cl 0H14N5O4P
Example 2 Synthesis of 3-[({l-[(6-amino-9-r--purin-9-yl)metbyl]cyclopropyl}oxy)methyl]- 8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 2)
The title compound was prepared according to the method known in a reference(see: J. Med. Chem., 37(12), 857 (1994)) and USP 5,663,159 (1998).
The compound prepared in Example 3 (3.00g) was dissolved in 350mA of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine- carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto. When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50mA of water and 50mA of toluene to separate the organic layer. The aqueous layer was extracted twice with 50mA of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography(eluent: meth--nol/dichloromethane= 1/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid.
Η N3VIR(500MHZ, CDC13) S 0.91 (m, 2H), 1.12 (m, 2H), 1.20 (m, 18H), 1.90 (br s, 2H), 3.90 (d, 2H), 4.32 (s, 2H), 5.65 (m, 4H), 8.14 (s, IH), 8.31 (s, IH) ESI: 528 (M+l)+, C22H34N5O8P Example 3 Synthesis of ({l-[(2-amino-6-chloro-9-r-T-purin-9-yl)-nethyl]cyclopropyl} oxy)methyl phosphonic acid(Compound 3)
The compound prepared in Example 1 (l.OOg) was dissolved in 150mA of dry dimethylformamide, and 2.08g(7.32 mmol) of N,N'-dicyclohexyl-4-morpholine- carboxamidine and 2.75g(18.3 mmol) of chloromethyl pivalate were added thereto.
When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50mA of water and 50mA of toluene to separate the organic layer. The aqueous layer was extracted twice with 50mA of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol/dichloromethane=3/20, v/v) to give 0.59g(Yield 32%) of the title compound as a white solid.
'H NMR(MeOH-d4) δ 1.00 (s, 2H), 1.07 (s, 2H), 3.94 (d, 2H), 4.52 (s, 2H), 9.50 (s, IH) ESI: 334 (M+l)+, C10H33C1N5O4P Example 4 Synthesis of ({l-[(2-amino-6-hydroxy-9.H-purin-9-y-)methylJcycIopropy.}oxy) metbylphosphonic acid(Compound 5)
The compound prepared in Example 3 (41mg) was dissolved in 5mA of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to give 37mg(Yield 95%) of the title compound as a white solid.
'H NMR(MeOH-d4) δ 0.98 (m, 2H), 1.06 (m, 2H), 3.92 (d, 2H), 4.45 (s, 2H),
, 9.20 (S, 1H) ESI: 316 (M+l)+, C10H14N5O5P
Example 5 Synthesis of ({l-[(2-amino-9-r- -p-ιrin-9-yl)methyl]cyclopropyl}oxy)methyl phosphonic acid(Compound 9)
The compound prepared in Preparation 6 (150mg) was dissolved in 15mA of tetrahydrofuran, 15mg of 5% palladium/carbon was added thereto, and the compound was reduced under 1 atm of hydrogen atmosphere for 18 hours. After completion of reaction, palladium/carbon was removed by suction filtration and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 130mg of diisopropyl compound ESI: 384(M+1)+, C16H26N504P). This compound was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 91mg(Yield 90%) of the title compound.
Η NMR(MeOH-d4) δ 0.94 (m, 2H), 1.03 (m, 2H), 3.93 (d, 2H), 4.40 (s, 2H), 8.66 (s, 3H), 8.74 (s, IH) ESI: 300 (M+l)+, C10H14N5O4P Example 6 Synthesis of 3-[({l-[(2-amino-9-r--purin-9-yl)methyl3cycIopropyl}oxy)methyI]- 8,8-dime-hyI-3,7-dioxo-2,4.6-triosa-3λ5-phosphanon-l-yI pivalate(Co-npoυnd 10)
The compound prepared in Example 5 was reacted according to the same procedure as Example 2 to give the title compound. Η MR(CDCl3-d4) δ 0.90 (m, 2H), 1.05 (m, 2H), 1.20 (m, 18H), 3.96 (d, 2H), 4.22 (s, 2H), 5.65 (m, 4H), 8.03 (s, IH), 8.69 (s, IH) ESI: 528 (M+l)+, C22H34N5O8P
Ex mple 7 Synthesis of ({l-[(2-amino-6-cyclopropylamino-9---T-purin-9-yl)methyl] cyclopropyl} oxy)methylphosphonic acid(Compound 11) The compound prepared in Preparation 6 (200mg) was dissolved in 20mA of ethanol, 53 mA of triethylamine and 82mg of cyclopropyla ine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 178mg(Yie3d 85%) of the diisopropyl compound.
Η NIV--R(CDC13) δ 0.59 (t, 2H), 0.83 (m, 4H), 1.00 (1, 2H), 1.24 (d, 6H), 1.29 (d, 6H), 3.0 (brs, IH), 3.80 (d, 2H), 4.15 (s, 2H), 4.70 (m, 2H), 4.71 (brs, 2H), 5.71 (s, IH), 7.68 (s, IH)
The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 3 to give 128mg(YieId 90%) of the title compound. Η NMR(MeOH-d4) δ 0.86 (m, 2H), 0.94 (m, 2H), 1.02 (m, 2H),1.07 (m, 2H), 2.90 (br s, IH), 3.93 (d, 2H), 4.39 (s, 2H), 8.43 (br s, IH) ESI: 355 (M+l)+, C13H19N604P
Example 8 Synthesis of ({l-[(2-amino-6-ethylamino-9-r-T-purin-9-yl)methyl]cyclopropyl} oxy) methylphosphonic acid(Compound 13)
The compound prepared in Preparation 6 (115mg) was dissolved in 20mA of ethanol, 33 mA of triethylamine and 0.07mA of ethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 104mg(Yield 89%) of the diisopropyl compound.
'H 3vlR(CDC-3) δ 0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H), 1.29 (d, 6H), 3.60 (brs, 2H), 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H), 5.50 (br s, IH), 7.78 (s, IH) The compound thus obtained was reacted according to the same procedure as Example 1 to give 75mg(Yield 90%) of thetitle compound.
Η NMR(MeOH-d4) δ 0.89 (m, 2H), 1.04 (m, 2H), 1.31 (t, 3H), 3.59 (br s, 2H), 3.92 (d, 2H), 4.35 (s, 2H), 9.95 (br s, IH) ESI: 343 (M+l)+, C13H19N604P
Example 9 Synthesis of [(l-{[2-amino-6-(dimethylamino)-9-H-purin-9-yl3methyl} cyclopropyl)oxy}methylphosphonic acid(Compound 15)
The compound prepared in Preparation 6 (115mg) was dissolved in 20-oA of ethanol, 38.6mA of triethylamine and 1.74mA of N,N-dimethylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours.- Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 119mg rJeld 83%) of the diisopropyl compound.
'H :NMR(CDC13) δ 0.75 (t, 2H), O.93 (t, 2H), l .16 ( 6H), 1.22 (d, 6H), 3.3 (bis, 6H), 3.74 (d, 2H), 4.09 (s, 2H), 4.60 (m, 2H), 4.69 (brs, 2H), 7.68 (s, IH)
The compound thus obtained was reacted according to the same procedure as Example 3 to give 86mg(Yield 90%) of the title compound. 'H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 3.30 (br s, 6H), 3.90 (d, 2H), 4.37 (s, 2H), 7.92 (br s, IH) ESI: 343 (M+l)+, C12H19N604P
Example 10 Synthesis of [(l-{[2-amino-6-(isopropylamino)-9--F-purin-9-yl]methyl} cyclopropyl) oxyjmethylphosphonic acid(Compound 17)
The compound prepared in Preparation 6 (133mg) was dissolved in 20mA of ethanol, 0.049mA of triethylamine and 0.082mA of isopropylamine were added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted whh ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichJoromethane/methanol=20/l, v/v) to give 95mg(Yield 68%) of the diisopropyl compound.
'H NMR(CDC13) δ 0.83 (m, 2H), 0.98 (m, 2H), 1.28 (m, 18H), 3.79 (d, 2H), 4.15 (s, 2H), 4.60 (br s, IH), 4.68 (s, 2H), 4.70 (m,' 2H), 5.40 (br s, IH), 7.77 (s, IH)
The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg(Yield 91%) of the title compound.
Η NMR(MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 1.34 (d, 6H), 3.30 (br s, IH), ' 3.90 (d, 2H), 4.36 (s, 2H), 8.01 (br s, IH) ESI: 357 (M+l)+, C12H19N604P
Example 11 Synthesis of ({l-[(2,6-diamϊno-9-r-7-purin-9-yl)methyI]cyclopropyl} oxy)methyl- phosphonic acid(Compound 19) The compound prepared in Preparation 4 (246mg) and 2,6-diaminopurine were reacted according to trie same procedure as Preparation 5 to give 78.5mgQfield 29%) of the diisopropyl compound.
Η NMR(CDC13) δ 0.85 (t, 2H), 1.00 (t, 2H), 1.25 (d, 6H), 1.29 (d, 6H), 1.83 (brs, 2H), 3.82 (d, 2H), 4.15 (s, 2H)S 4.68 (m, 2H), 5.39 (d, 2H), 7.85 (s, IH) ESI: 399 (M+l)+, C16H27N604P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 72mg(Yield 91%) of the title compound.
]H NMR(DMS0-d6 + CF3COOH) δ 0.70 (m, 2H), 0.82 (m, 2H), 3.58 (d, 2H), 4.21 (s, 2H), 8.16 (br s, IH) ESI: 315 (M+l)+, C10H15N6O4P Example 12 Synthesis of ({l-[(2-amino-6-ethoxy-9-r7-purin-9-yI)methyI]cyclopropyl}oxy) methylphosphonic acid (Compound 23)
6-Chlorogu--nine derivative prepared in Preparation 6 (lOOmg) was dissolved in 10 mA of ethanol, 32mA of triethylamine and 53 mg of sodium methoxide were added, and the resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10mA of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified by silica gel column to give a compound wherein 6-position of guanine was substituted by ethoxy group.
ΗNMR(CDCi3) δ 0.83 (t, 2H), 1.00 (t, 2H), 1.24-1.28 (m, 12H), 1.45 (t, 3H), 3.82 (d, 2H), 4.21 (s, 2H), 4.53 (m, 2H), 4.67 (m, IH), 5.76 (s, 2H), 7.90 (s, IH)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
'H NMR(MeOH-d4) δ 0.99 (t, 2H), 1.06 (t, 2H), 1.48 (t, 3H), 3-91 (<*, 2H), 4.51 (s, 2H), 4.65 (m, 2H), 9.18 (s, IH) ESI: 344 (M+l)+, C12H18N5O5P
Example 13 Synthesis of ({l-[(2-amino-6-methyl-9-r7-purin-9-yI)methyl3cyclopropyI}oxy) methylphosphonic acid(Compound 25) 30mA flask was dried under vacuum and 53mg(0.238mmol) of zinc bromide was introduced bit by bit under nitrogen atmosphere. 2mA of diy tetrahydrol r--n was added dropwise thereto, the temperature was lowered to -78 , 0.08mA(20.238mmol) of • methylmagnesium Grinard was added, and the resulting mixture was stirred for 1 hour. After the reaction mixture was warmed to room temperature, about 10mol% of palladiumtetrakistriphenylphosphine was added bit by bit. 50mg(0.119mmol) of the compound prepared in Preparation 6 in 1mA of tetrahydrofuran was added to the above reaction solution dropwise. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the residue was participated with water and ethyl acetate, and the organic layer was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography(eluent: methylene chloride/methanol=90/10, v/v) to give 20mg(Yield 42%) of the diisopropyl compound.
Η NMR(MeOH-d4) δ 0.95 (m, 2H), 0.98(m, 2H), 1.17(d, 6H), 1.23 (d, 6H), 2.59(s, 3H), 4.02(s, IH), 4. 0(s, IH), 4.32(s, 2H), 4.59(m, 2H), 8.12(s, IH) ESI: 398 (M+l)+, C17H28N504P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 8.0mg(Yield 50%) of the title compound.
Η NMR(D20) δ 0.87 (m, 2H), 1.02 (m, 2H), 3.79 (s, IH), 3.81 (s, IH), 4.53 (s, 2H), 8.25 (s, IH) ESI: 314 (M+l)4, Cl 1H16N504P Example 14 • Synthesis of [(l{[5-methyl-2J4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl]methyl} cyclopropyI)oxy]0iethylphosphonic acid(Compound 31)
The compound prepared in Preparation 7 (19mg) was reacted according to the same procedure as Example 1 to give 34mg(Yield 95%) of the title compound.
ESI: 291 (M+l)+, C10H11N206P Η NMR(MeOH-d4) 6 0.82 (t, 2H), 0.97 (t, 2H), 1.87 (s, 3H), 3.83 (d, 2H), 3.97 (s, 2H), 7.55 (s, IH) Example 15 Synthesis of [(l-{[2-amino-6-(4--norphoHnyl)-9£T-purin-9-yI3methyl} cyclopropyJ)oxy]methylphosphonic acid(Compoυnd 37) The compound prepared in Preparation 6 (134rog) was dissolved in 20mA of ethanol, 0.049mA of triethylamine and 0.085mA of morpholine were added thereto, and the , resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethanemethanol=20/l, v/v) to give 66mg(Yield 44%) of the diisopropyl compound.
■H NMR(CDC13) 6 0.83 (m, 2H), 0.99 (m, 2H), 1.24 (d, 6H), 1,30 (d, 6H), 3.79 (m, 6H), 4.18 (s, 2H), 4.21 (br s, 4H), 4.67 (m. 2H), 4.80 (br s, 2H), 7.78 (s, IH) ESI: 469 (M+ϊ)+, C20H33N6O5P
The compound thus obtained was treated with trimethylsilylbromide according to the same procedure as Example 1 to give 49mg(Yield 91%) of the title compound. !H NMR(MeOH-d4) δ 0.89 (m, 2H), 1.07 (m, 2H), 3.81 (m, 4H), 3.92 (d, 2H), 4.40(br s, 6H), 7.87 (s, IH) ESI: 384 (M+l)+, C14H21N605P
Example 16 Synthesis of [(l-{[2-amino-6-(l-piperidinyl)-9r-f-purin-9-yI}methyl} cyclopropyl)oxy]methylphosphonic acid(Compound 39) the compound prepared in Preparation 6 (154mg) was dissolved in 20mA of ethanol, 0.049mA of triethylamine and 0.11mA of piperidine were added thereto, and the resulting mixture was heated under reflux for 38 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give 123mg (Yield 72%) of the diisopropyl compound. Η M ^DCl,) δ 0.80 (m, 2H), 0.99 (m, 2H), 1.22 (d, 6H), 1.26 (d, 6H), 1.63 ( , 4H), 1.67 (m, 2H), 3.78 (d, 2H), 4.14 (s, 6H), 4.54 (br s, 2H), 4.65 (m, 2H), 7.72 (s, IH) ESI: 467 (M+l)+, C21H35N6O4P 5 The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg(Yield 91%) of the title compound.
Η NMR(MeOH-d4) δ 0.89 ( , 2H), 1.06 (m, 2H), 1.73 (m, 4H), 1.79 (m, 2H), 3.90 (d, 2H), 4.37 (s, 2H), 4.43(br s, 4H), 7.89 (s, IH) ESI: 383 (M+l)+, Cl 5H23N604P
Example 17 Synthesis of [(l-{[2-amino-6-(4-methyl-l-piper----inyI)-9-Sr-purin-9-yI]nιethyI} cyclopropyl)oxy]methylphosphonic acid(C mpound 41)
The compound prepared in Preparation 6 (128mg) was dissolved in 20mA of ethanol, 0.10mA of 4-methyl-l-piperazine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product. was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give 123mg(Yield 83%) of the diisopropyl compound. -Η NMR(CDC13) δ 0.80 (m, 2H), 0.98 (m, 2H), 1.21 (d, 6H), 1.27 (d, 6H), 2.30
' (s, 3H), 2.48 ( , 4H), 3.78 (d, 2H), 4.13 (s, 2H), 4.22 (br s, 4H), 4.57 (s, 2H), 4.66 (m, 2H), 7.73 (s, IH) ESI: 482 (M+l)+, C21H36N704P The compound thus obtained was reacted according to the same procedure as Example 1 to give 87mg(Yield 85%) of the title compound.
]H δ 0.89 ( , 2H), 1.07 (m, 2H), 3.00 (s, 3H), 3.72 (m, 4H), 3.91 (d, 2H), 4.45 (s, 2H), 4.89 (m, 2H), 5.70 (br, 2H), 7.91 (s, IH) ESI: 398 (M+1)+, CT5H24N704P Example 18 Synthesis of r(l-{P-amino-6-(l-pyrrolidinyl)-9Zr-purin-9-yl]methyl} cycIopropyl)oxy]methyl phosphonic acid (Compound 43)
The compound prepared in Preparation 6 (322mg) was dissolved in 20mA of ethanol, 0.07mA of pyrrolidine was added thereto, and the resulting mixture was heated under reflux for 18 hours. Water was added to stop the reaction, and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified by silica gel column chromatography(eluent: --ichlorometh-uιe/methanol=20/l, v/v) to give H0mg(Yi'eld 83%) of the diisopropyl compound.
JH NMR(CDC13) δ 0.78 (m, 2H), 0.96 (m, 2H), 1.20 (d, 6H), 1.26 (d, 6H), 2.00 (br s, AH), 3.60 (br, 3H), 3.78 (d, 2H), 4.09 (br, 2H), 4.12 (s, 2H), 4.63 (m, 2H), 7.69 (s, IH) ESI: 453 (M+l)+, C20H33N6O4P
The compound thus obtained was reacted according to the same procedure as Example 1 to give 76mg(Yie3d 85%) of the title compound.
Η NMR(MeOH-d4) δ 0.94 (m, 2H), 1.03 (a, 2H), 2.15 (m, 4H), 3.76 (m, 2H), 3.93 (d, 2H), 4.18 (in, 2H), 4.40 (s, 2H), 5.70 (br, 2H), 8.42 (s, IH) ESI: 369 (M+l)+, C14H21N6O4P
Example 19 Synthesis of 3-[({l-I(2-an-ino-9-r-T-purinτ9-yl)methyl]cycJopropyl}oxy) methyl) -9-metby--3,7-dioxo-2,4,6-trioxa-3λs-phosphadec-l-yl 3-methylbutanoate (Compound 74) ' The compound prepared in Example 5 (lOO g) was dissolved in dimethylformamide (2mA) and then reacted with chloromethyl 3-methylbutyrate in the presence of triethylamine (3 equivalents) at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 1%. >H NMR(CDC13) δ 0.89 (t, 2H), 0.94 (d, 12H), 1.04 (t, 2H), 2.10 (m, 2H), 2.22 (d, 4H), 3.97 (d, 2H), 4.23 (s, 2H), 5.21 (s, 2H), 5.65 (m, AH), 8.00 (s, IH), 8.69 (s, IH) ESI: 527 (M+l)+, C23H35N408P
5 Example 20 Synthesis of 3-[({l-[(2-amino-9i-r-purin-9-y!)methyI]cycIopropyI}oxy) methyl] -3,7-dioxo-2,4,6-trioxa-3λ*-phosphadec-l-yI bu-yrate(Compound 75)
> The compound prepared in Example 5 was reacted with chloromethyl butyrate 10 according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 24%.
'H NMR(CDC13) δ 0.88 (t, 2H), 0.92 (d, 6H), 1.60 (m, 4H), 2.32 (t, 4H), 3.96 (d, 15 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.62 (in, 4H), 8.00 (s, IH), 8.68 (s, IH) ESI: 499 (M+l)+, C21H31N408P
Example 21 Synthesis of 3-[C{l-[(2-amino-9-er-purin-9-yl)methylJcyclopropyI}oxy) methylj-0 ' 8-methy--3J7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl 2-methylpropanoate (Compound 78)
The compound prepared in Example 5 was reacted with chloromethyl isobutyrate according to the same procedure as Example 19 at room temperature for 24 hours. The5 resulting product was purified by silica gel column to give the title compound in a yield of 21%.
JH NMR(CDCi3) δ 0.84 (t, 2H), 0.97 (t, 2H), 3.11 (d, 12H), 2.52 ( , 2H), 3.91 (d, 2H), 4.16 (s, 2H), 5.21 (s, 2H), 5.58 (m, AH), 7.96 (s, IH), 8.61 (s, IH) ESI: 499 (M+l)+, C21H31N408P
Example 22 Synthesis of 3-[({l-[(2-amino-9-r-T-purin-9-yl)methyl]cyclopropyl}oxy) methyl] , -3,7-dioxo-7-(l-pyrroIidinyl)-254,6-trioxa-3λs-phosphahept-l-yl pyrrolidinecarboxylate (Compound 80) The compound prepared in Example 5 was reacted with chloromethyl 1- pyrrolidinecarboxylate. according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 35%.
]HNMR(CDC13) δ 0.82 (t, 2H), 0.87 (m, 8H), 0.98 (t, 2H), 1.57 (d, 4H), 2.26 (t, 4H), 3.91 (d, 2H), 4.16 (s, 2H), 5.12 (s, 2H), 5.57 ( , 4H), 7.98 (s, IH), 8.62 (s, IH) ESI: 553 (M+l)+, C23H33N608P
Example 23 Synthesis of 3-[({l-[(2-amino-9-Br-purin-9-yI)methyI]cyclopropyl}oxy) metbyl]- 3,7-dioxo-7-(l-piperidiny])-2,4,6-trioxa-3λδ-phosphahepM-yl 1- piperidinecarboxyIate(Compound 81);
The compound prepared in Example 5 was reacted with chloromethyl 1- piperidinecarboxylate according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title compound in a yield of 39%.
Η NMR(CDCI3) δ 0.86 (t, 2H), 3.02 (t, 2H), 1.47-1.58 (brm, 32H), 3.40 (bπn, 8H), 3.99 (d, 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.69 (m, 4H), 8.00 (s, IH), 8.67 (s, IH) ESI: 581 (M+l)+, C25H37N608P
Example 24 Synthesis of 3-[({l-f(2-amino-9^-purin-9-yI)methyl}cyclopropyl}oxy) methyl]- 7-(4-morphoIiny])-3,7-dioxo-2,456-trioxa-3λs-phosphahept-l-yl 4_ morpholinecarboxylate(Compound 82)
The compound prepared in Example 5 was reacted with chloromethyl 4- orpholinecarboxylate" according to the same procedure as Example 19 at room temperature for 24 hours. The resulting product was purified by silica gel column to give the title. compound in a yield of 40%. Η N- ttKCDCla) δ 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H),.3.65 (bπn, 8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, AH), 8.07 (s, IH), 8.69 (s, IH ESI: 586 (M+l)+, C23H33N6010P
5 Example 25 Synthesis of {[l-^-amino-fi-^-methylpheny sulfanylJ- -r-T-purin-J-yl} methyl)cyclopropyl]oxy}methylphosphonic acid(Compoυnd 66)
6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85
10 mA of methanol and 1.4g of triethylamine and 2.9g of 4-methylthiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20mA of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified ' by silica gel column to give a compound wherein 6-position of guanine was substituted by
15. 4-methylphenylthio group.
Η -Sr3V-R(CDCl3) δ 0.84 (t, 2H), 1.02 (t, 2H), 1.25-1.31 (m, 12H), 2.40 (s, 3H), 4.20 (d, 2H), 4.69 (m, 2H), 4.74 (s, 2H), 7.22 (d, 2H), 7.50 (d, 2H), 8.00 (s, IH) 0 The compound thus obtained was reacted according to the same procedure as Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the title compound.
'H NMR(MeOH-d4) δ 0.98 (t, 2H), 1.06 (t, 2H), 2.42 (s, 3H), 3.92 (d, 2H), 4.485 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H), 9.05 (s, IH) ESI: 421 (M+l)+, C18H21N404PS i Example 26 Synthesis of 3-({[l-({2-amino-6-[(4-methylphenyl)suIfanyl]-9-r-r-purin-9-yl}0 methyl)cycIopropyI]oxy}methyl)-8,8-dimethyI-3,7-dϊoxo-2,4,6-trioxa-3λ -phospbanon- 1-yl pivaFate(Compound 68)
The methylphosphonic acid prepared in Example 25 was reacted according to the same procedure as Example 2 to give the title compound. ΗNMRCCDC-a) δ 0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s, 3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d, 2H), 7.48 (d, 2H), 7.88 (s, IH) ESI: 649 <M+1)+, C30H41N4O8PS Example 27 Synthesis of {[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9-ϊ--purin-9-yl} methyI)cyclopropyl]oxy}methylphosphonic acid(Compoυnd 96)
6-Chloroguanine derivative prepared in Preparation 6 (4.86g) was dissolved in 85 mA of methanol and 1.4g of triethylamine and 2.9g of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20mA of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-pόsition of guanine was substituted by 4-methoxyphenylthio group.
The compound thus obtained was reacted according to the same procedure as i Example 1 and then recrystallized from a mixture of methanol-diethylether (1/20, v/v) to give the ύύe compound.
'H NMR(MeOH-d4) δ 0.77 (m, 2H), 1.05 (m, 2H), 3.87 (s, 3H), 3.92 (d, 2H), 4.45 (s, 2H), 7.10 (d, 2H), 7.59 (d, 2H), 8.09 (s, IH) ESI: 438 (M+l)+, C17H20N5O5PS Example 28 Synthesis of {[l-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9-Hr-purin-9-yϊ}methyl) cyclopropyI}oxy}methylphosphonic acid(Compound 95)
The compound prepared in Preparation 6 was reacted according to the same procedure as Example 27 except that 4-nitrothiocresol was used insteSad of 4- methoxythiocresol to give the title compound.
Η NMR(MeOH-d4) δ 0.86 (m, 2H), 0.95 (m, 2H), 3.82 (d, 2H), 4.35 (s, 2H), 7.81 (d, 2H), 8.22 (d, 2H). 8.72 (s, IH) ESI: 453 (M+l)+, C16H17N6O6PS Example 29 Synthesis of ({l-[(2-amino-6-hydroxy-9-r-T-purin-9-yl)methyl]-2--nethyI cydopropyl}oxy)methylphosphonic acid(Compound 97)
The 6-chloroguanine derivative prepared in Preparation 12 was consecutively reacted according to the same procedure as Examples 3 and 4 to give the title compound.
,HNMR(MeOH-d4) 8 0.73 (t, IH), 1.15 (m, IH), 1.21(d, 3H), 1.38 (t, IH), 1.48 (m, IH), 3.85 (t, IH), 3.96 (t, IH), 4.42 (d, IH), 4.69 (d, IH), 9.12 (s, IH)
Example 30 Synthesis of {[l-({2-amino-I6-(4-methoxyphenyI)sulfanyI]-9-?7-purin-9-yl} metbyl)-2-nιethylcycIopropyl]oxy}methylphosphonic acid(Compound 99)
The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 27 to give, the title compound.
Η NMR(MeOH-d4) δ 0.67 (t, IH), 1.13 (m, 2H), 1.20 (d, 3H), 1.45 (m, IH), 3.85 (m, IH), 3.86 (s, 3H), 3.94 (m, IH), 4.42 (d, IH), 4.68 (d, IH), 7.09 (d, 2H), 7.59 (d, 2H), 9.00 (s, IH) ESI: 452 (M+l)+, Cl 8H22N505PS
Example 31 Synthesis of {[l-({2-amino-I6-(4-methyIphenyl)sulfanyI]-9jr7-purin-9-yl} methyl)-2-methylcycIopropyl]oxy}methylphosphonic acid(Compound 101)
The 6-chlorogu--nine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 25 to give the title compound.
Η NMR(MeOH-d4) δ 0.68 (t, IH), 1.35 ( , 2H), 1.20 (d, 3H), 1.45 (m, IH), 2.42 (s, 3H), 3.84 ( . IH), 3.96 (m, IH), 4.43 (d, IH), 4.68 (d, IH), 7.36 (d, 2H), 7.55 (d, 2H), 9.05 (s, IH) ESI: 436 (M+l)+, C38H22N504PS Example 32 Synthesis of {[l-({2-amino-[6-(4-nitrophenyI)sulfanyl]-9-H-purin-9-yl}nιethyI) -2-methylcyclopropyl]oxy}methylphosphonic acid(Compound 100) The .6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 28 to give the title compound.
Η NMR(MeOH-d4) δ 0.49 (t, IH), 0.93 ( , IH), 1.00 (d, 3H), 1.25 (m, IH), 3.64 (m, IH), 3.76 (m, IH), 4.28 (d, IH), 4.53 (d, IH), 7.72 (d, 2H), 8.14 (d, 2H), 9.10 (s, IH) ESI: 467 (M+l)+, C17H19N606PS
Example 33 Synthesis of ({l-[(6-amino-9fl'-purin-9-yI)methyI]-2--nethylcyclopropyI}oxy) methylphosphonic acid(Compound 103)
The adenine derivative prepared in Preparation 11 was reacted according to the Same procedure as Example 1 to give the title compound. Η NMR(MeOH-d4) δ 0.64 (t, IH), 1.09 (m, IH), 1.20 (d, 3H), 1.43 (m, IH), 3.83 (m, IH), 3.95 (m, IH), 4.49 (d, IH), 4.75 (d, IH), 5.49 (s, 2H), 8.39 (s, IH), 8.55 (s, IH) ESI: 314 ( +l)+, C11H16N504P Example 34 Synthesis of bis{[(t-butoxycarbonyI)oxy]njethyl}({l-[(2-amino-9-9-purin-9-yl) methyI]cyclopropyI}o--y)methyIphosphonate(Co-npound 69)
The compound prepared in Example 5 (387mg) was mixed with 6mA of N-methyl- 2-pyrrolidone, and 300mg of triethylamine and 150mg of chloromethyl t-butyl carbonate were added. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10mA of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound. ΗNMR(CDC13) δ 0.86 (m, 2H), 1.06 (ra, 2H), 1.47 (s, 18H), 4.01 (d, 4H), 4.22 , (s, 2H), 5.00 (brs, 2H), 5.61 (m, 4H), 7.99 (s, IH), 8.69 (s, IH) ESI: 344 (M+l)+, C22H34N5O10P Example 35 Synthesis of bis{[(isopropo--ycarbonyl)o--y3 ethyl}({l-[(2-amino-9---T-purm- 9- yI)methyI]cycIopropyI}oxy)methylphosphonate(Compound 70)
The compound prepared in Example 5 (lOOmg) was mixed with 5mA of N-methyl- 2-pyrroh'done, and 1 lOmg of triethylamine and 150mg of chloromethyl isopropylcarbonate were added. The reaction solution was stirred at 50 for 4 hours. The reaction was stopped by adding 10mA of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and purified by silica gel column to give the title compound.
ΗNMR(CDC13) 6 0.88 (s, 2H), 1.06 (s, 2B), 1.29 (d, 2H), 1.31 (d, 2H), 4.01 (d, AH), 4.21 (s, 2H), 4.92 (m, 2H), 5.01 (brs, 2H), 5.64 (m, AH), 7.99 (s, IH), 8.69 (s, IH) ESI: 532 (M+l)+, C20H30N5O10P Example 36 Synthesis of ({l-[(2-amino-6-hydroxy-9-fiT-purin-9-yl)nιethyI]-2,2-dimethyl cyclopropyl}oxy)methylphosphonic acid(Coπ-pound 146)
The compound prepared in Preparation 32 was consecutively reacted according to the same procedure as Examples 1 and 4 to give the title compound.
'H NMR(MeOH-d4) δ 0.78 (d, IH), 0.82 (d, 3H), 1.21 (s, 3H), 1.27 (s, 3H), 3.90 (d, IH), 3.91 (d, IH), 4.58 (s, 2H), 9.12 (s, IH) ESI: 344 (M+l)+, C12H18N505P
Example 37 Synthesis of ({l-[(2-amino-9-r-T-purin-9-yJ)methyI]-2,2-dimethylcyclopropyI} oxy)metbylpbosphonic acid(Compoυnd 147) The compound prepared in Preparation 32 was reacted according to the same procedure as Example 5 to give a compound wherein 6-position of guanine was reduced by hydrogen.
'H NMR(CDC13) δ 0.60 (d, IH), 0.82 (d, IH), 1.21 (s, 3H), 1.22 (s, 3H), 1.22 (m, 5 15H), 3.73 (m, IH), 3.87 (m, IH), 4.13 (d, IH), 4.49 (d, IH), 4.67 (m, 2H), 4.98 (brs, 2H), 8.09 (s, IH), 9.67 (s, IH)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.0 'H NMR(MeOH-d4) 6 0.74 ( , IH), 0.81 (d, IH), 1.21 (s, 3H), 1.26 (s, 3H), 3.91 (d, 2H), 4.49 (d, IH), 4.57 (d, IH), 8.63 (s, IH), 8.74 (s, IH) ESI: 328 (M+l)+, C12H18N504P Example 38 Synthesis of ({l-l(6-amino-9flr-purin-9-y-)methy-]-2 -dimethyIcyclopropyl} o--y)methylpbosphonic acid(Compound 148)
The compound prepared in Preparation 31 was reacted according to the same procedure as Example 1 to give the title compound.
Η NMR(MeOH-d4) δ 0.77 (d, IH), 0.79 (d, IH), 1.25 (s, 3H), 1.28 (s, 3H), 3.90 (d, 2H), 4.61 (d, IH), 4.70 (d, IH), 8.38 (s, IH), 8.51 (s, IH) ESI: 328 (M+l)+, C12H18N504P
Example 39 Synthesis of (JEi)-2-{l-[(2-amino-6-hydroxy-9jr-f-purin-9-yl)-nethyl]cyclopropyl} ethenylphosphonic acid(Compound 130) The compound prepared in Preparation 26 was reacted according to the same procedure as Example 1 to give phosphonic acid derivative.
Η NMR(MeOH-d4) δ 1.07 (t, 2H), 1.33 (t, IH), 4.41 (s, 2H), 5.76 (dd, IH), 6.45 (dd, 3H), 9.38 (s, 3H), The compound thus obtained was reacted according to the same procedure as Example 4 to give the title compound.
•H N- R(MeOH-d4) δ 1.08 (t, 2H), 1.34 (t, IH), 4.38 (s, 2H), 5.78 (dd, IH), 6.46 (dd, lH), 9.11 (s, lH) ESI: 312 (M+l)+, Cl IH14N504P
Example 40 Synthesis of 2-{l-I(2-amino-9J- -purin-9-yϊ)_nethyl]cyclopropyl}ethyl phosphonic acid(Compound 139)
The compound prepared in Preparation 26 was reacted according to the same procedure as Example 5 to give the title compound. Η NMR(MeOH-d4) δ 0.58 (t, 2H), 0.85 (t, 2H), 1.42 (m, 2H), 1.95 (m, 2H), 4.11 (s, 2H), 5.78 (dd, IH), 8.55 (s, IH), 8.75(s, IH) ESI: 298 (M+l)+, Cl 1H16N503P
Example 41 Synthesis of (-E)-2-{l-[(6-amino-9--J-purin-9-yl)metbyl]cyclopropyl}ethenyI phosphonic acid(Compound 132)
The compound prepared in Preparation 25 was reacted according to the same procedure as Example 1 to give the title compound.
'H NMR(MeOH-d4) δ 0.94 (t, 2H), 1.20 (t, 2H), 4.36 (s, 2H), 5.63 (dd,- IH), 6.37 (dd, IH), 8.30 (s, IH), 8.31 (s, IH) ESI: 296 (M+l)+, Cl 1H14N503P Example 42 Synthesis of 2-{l-[(6-amino-9-r-T-purin-9-yl)methyl]cyclopropyl}ethyI phosphonic acid(Compound 140)
The compound prepared in Preparation 25 was reacted according to the same procedure as Example 5 to give the title compound. 'H NMR(MeOH-d4) δ 0.58 (t, 2H), 0.87 (t, 2H), 1.37 (m, 2H), 1.97 (m, 2H), 4.24 (s, 2H), 8.31 (s, IH), 8.42 (s, IH) ESI: 298 (M+l)+, Cl 1H16N503P 5 Example 43 Synthesis of 2-{l-[(2-amino-6-hydroxy-9-εr-purin-9-yl)methyl]cyclopropyl} ethylphosphonic acid(Compound 138) The compoimd prepared in Preparation 26 was reacted according to the same procedure as Example 12 to give a compound wherein 6-position of guanine was substituted by ethoxy group.
Η NMR(CDC13) 6 1.00 (t, 2H), 1.10 (t, 2H), 1.16-1.21 (m, 9H), 3.90 (m, 4H), 4.01 (m, 2H), 4.13 (s, 2H), 4.92 (s, 2H), 5.58 (dd, lB),-6.49 (dd, IH), 7.62(s, IH)
The compound thus obtained (80mg) was dissolved in methanol and reacted under . hydrogen atrmo sphere in the presence of 20mg of 10% Pd/C to give a compound wherein double bond was reduced.
Η --R(CDCl3) 6 0.49 (t, 2H), 0.66 (t, 2H), 1.21 (t, 6H), 1.42 ( , 2H), 2.01 (m, 2H), 3.99 (m, 6H), 4.96 (s, 2H), 7.59 (s, IH)
The compound thus obtained was reacted according to the same procedure as Example 1 to give the title compound.
Η NMR(MeOH-d4) δ 0.60 (t, 2H), 0.87 (t, 2H), 1.47 (in, 2H), 1.97 (m, 2H), 4.16 (s, 2H), 9.12 (s, lH) ESI: 314 (M+l)+, Cl 1H16N504P ' Example 44 Synthesis of 2-{l-[(2-amino-9-r7-purin-9-yl)metby-]cycIopropy-}propyI phosphonic acid(Compoυnd 144) The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 26 and Example 5 to give the title compound.
'H NMR( eOH-d4) δ 0.62-0.77 (m, 4H), 1.04 (d, 3H), 1.52 (m, 2H), 1.90 (m, IH), 4.24 (m, 2H), 8.58 (s, IH), 8.74 (s, IH) ESI: 312 (M+l)+, C12H18N503P
Example 45 Synthesis of (£)-2-{l-[(6-a ino-9-r--purin-9-yl)methyl]cyclopropyl}-l- propenylphosphonic acid(Compound 137)
The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 1 to give the title compound.
ΗNMR(MeOH-d4) δ 0.86 (t, 2H), 1.10 (t, 2H), 2.19 (d, 3H), 4.38 (s, 2H), 5.23 (d, IH), 8.34 (s, IH), 8.37(s, IH) ESI: 310 (M+l)+, C12H16N5O3P
Example 46 Synthesis of 2-{l-[(6-amino-9----r-purin-9-yl)methyI]cyclopropyl}propyl phosphonic acid(Compoυnd 143) « The compound prepared in Preparation 35 was consecutively reacted according to the same procedure as Preparations 24, 25 and Example 5 to give the title compound. TH NMR(MeOH-d4) δ 0.65 (t, 2H), 0.78 (t, 2H), 0.95 (m, IH), 1.00 (d, 3H), 1.53 (s, IH), 1.90 (m, IH), 4.3 (q, 2H), 8.41 (s, IH), 8.45 (s, IH) ESI: 312 (M+l)+, C12H18N503P
Example 47 Synthesis of b-s(2a2,2-trifluoroethyl) ({l-[(6-amino-9F-purin-9-yl)methyl] cyclopropyl} oxy)methyIphosphonate(Compound 48)
To the methylphosphonic acid prepared in Example 1 (150mg) was added dropwise dichloromethane, 0.73mA of - N-diethyltrimethylsilylamine was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. Oxalyl chloride (0.15mA) and 2 drops of dimethylformamide were added to the reaction vessel. The mixture was stirred for further 2 hours and the solvent was removed by distillation under reduced pressure. To the residue were added 10mA of pyridine and 2mA of trifluoroethanol, which was then reacted under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column to give the title compound.
• 'H N3vIR(CD3OD) δ 1.02 (m, 4H), 4.30 (d, 2H), 4.53 (m, 6H), 8.40 (s, IH), 8.46(8, IH) ESI: 464 [M+H3+: C14H16F6N5O4P
Example 48 Synthesis of bis(2,2,2-trifluoroethyl) ({l-[(2-amino-9-ff-purin-9-yl)methyl] cyclopropyl} oxy)mεthylphospbonate(Compoun 49)
The compound prepared in Example 5 was reacted- according to the same , procedure as Example 47 to give the title compound.
]HNMR(CDC13) δ 0.88 ( , 2H), 1.04 (m, 2H), 4.07 (d, 2H), 4.22 (s, 2H), 4.33 (m, 4H), 5.06 (br.s, 2H), 7.92 (s, IH), 8.68 (s, IH) ESI: 464 IMrø]+, C14H16F6N5O4P
Example 49 Synthesis of bis(2,2,2-trifluoroethyl) ll-({2-amino-I6-(4-metbylphenyI) ' sulfanyl]-9-f-r-purin-9-yl}metbyl)cyclopropyl]oxy}methylphospbonate(Co-npound 62)
The compound prepared in Example 25 was reacted according to the same procedure as Example 47 to give the title compound. 'H NMR(CDC13) δ 0.88 (m, 2H), 1.03 (m, 2H), 2.39 (s, 3H), 4.06 (d, 2H), 4.19 (s, 2H), 4.33 ( , AH), 4.76 (br.s, 2H), 7.22 (d, 2H), 7.50 (d, 2H), 7.82 (s, IH) ESI: 586 [M+HQ+, C21H22F6N5O4PS
Example 50 Synthesis of bis(2,2,2-trifluoroethyl) [(l-{[2-amino-6-hydroxy-9jr-T-purin-9-yI] methyl}cyclopropyI)oxy]methylphosphonate(Compound 45)
The compound prepared in Example 4 was reacted according to the same procedure as Example 47 to give the title compound.
Η NMR(CDC13) δ 0.91 (m, 2H), 1.05 ( , 2H), 4.08 (d, 2H), 4.17 (s, 2H), 4.35 (m, 4H), 4.70 (s, 2H), 7.69 (s, IH) MW=478 [M+H]+ 479 C14H16F6N5O5P Example 51 Synthesis of bϊs(2,2,2-trifluoroethyl)(l-{[2-amino-6-cyclopropylamino- 9-BT- purin-9-yl]methyl}cycIopropyl)oxy]methylphosphonate(Compound 50)
The compound prepared in Example 7 was reacted according to the same ' procedure as Example 47 to give the title compound.
Η MR(CDC13) δ 0.60 (br.s, 2H), 0.84 (br.s, 4H), 1.01 ( , 2H), 2.98 (br.s, IH), 4.05 (d, 2H), 4.14 ( , AH), 4.70 (br.s, 2H), 5.67 (br.s, IH), 7.60 (s, IH) ESI: 519, [M+H]+, C17H21F6N604P
Example 52 Synthesis of ({l-[(2-amino-9-f-T-purin-9-yl)methyl]-2-methyIcycIopropyl}oxy) methylphosphonic acid(Compoυnd 98) The 6-chloroguanine derivative prepared in Preparation 12 was reacted according to the same procedure as Example 5 to give the title compound.
Η NMR(MeOH-d4) δ 0.68 (t, IH), 1.13 (m, IH), 1.21 (d, 3H), 1.42 (t, IH), , 3.84 (t, IH), 3.97 (t, IH), 4.40 (d, 3H), 4.66 (d, 3H), 8.63 (s, IH), 8.73 (s, IH) ESI: 314 (M+l)+, Cl 1H16N5O4P β er-menLlϊ
Measurement of Inhibition Effect against Human Immunodeficiency Virus (HIV) The compounds of formula 1 protect cells from the cytopathic effects of HIV infection. This activity was demonstrated in the following assay systems and Table 8. Cells. The T-lymphoblastoid cell line CEM was used in this study to propagate HIV. The cells were maintained in RPMI 1640 growth medium supplemented with 10% fetal bovine serum plus antibiotics. The CD4-expressing cell line used for HIV plaque assays, HT4-6C, was made by transforming HeLa cells with the human CD4 gene as described in Chesebro and Wehrly, J. Virology, 62(10), 3779-3788 (1988). These cells were grown in Dulbecco modified eagle medium (DMEM) containing 10% fetal bovine serum plus antibiotics. Virus propagation. The laboratory strain of HIV-1 (NL4-3) was grown in CEM cells. Virus stocks were prepared from cleared lysates of concentrated infected cells. At peak cytopathic effect (generally 5 days post-infection) culture supernatants were harvested and stored at - 80°C. Viral infectivity titers were determined in threefold endpoint dilution assays conducted in CEM cells (six wells per dilution). The 50% tissue culture infective dose (TCIDjo) was calculated using the Reed and Muench equation. Plaque titration using HT4-6C. Cells are seeded into 24-well multiwells at 5 x 104 cells per well and incubated overnight at 37°C in growth medium (DMEM containing 10% fetal bovine serum plus antibiotics). Monolayers were infected with 10-fold dilutions of cell-free NL4-3 virus in 0.2 ml of DMEM and were incubated for 1 h at 37°C to allow virus adsorption. Following this, 0.8 ml of DMEM containing 5% fetal bovine serum plus antibiotics was added to each well, and the cultures were incubated at 37°C for 2 to 3 days. The monolayers were fixed with a 10% formaldehyde solution in phosphate-buffered saline and stained with 0.25% crystal violet in order to visualize virus plaques. Individual foci of multinucleated giant cells (plaques) are obvious when this staining procedure was used. Virus titers were evaluated from plaque numbers and were expressed as PFU per milliliter. Drug susceptibility assays. Plaque reduction assays were performed by infecting monolayers of HT4-6C cells with 300 to 300 PFU of virus per well in 24-well microdilution plates as described above. Half-log concentrations of inhibitor were added to the culture medium (DMEM containing 5% fetal bovine serum plus antibiotics), and cultures were incubated for 3 days at 37°C prior to fixation and staining as described above. ID50S were derived from plots of percentage of plaque reduction versus inhibitor concentration. See Larder et al., Antimicrob Agents Chemother, 34(3), 436-41 (March 1990). Table 8

Claims

A method for treating a HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a formula 1 compound
in which 10 lϊS= represents single bond or double bond, R1, R2, R3, R7 and R* independently of one another represent hydrogen, halogen, hydroxy, amino, C,-C7-alkyl, C2-C6-alkenyl, C,-Cj-alkylamino, C,-Cj-aminoalkyl, or C,-C5-alkoxy, R4 and Rs independently of one another represent hydrogen, or represent C,-C_,-alkyl • ' 15 optionally substituted by one or more substituents selected from the group consisting of halogen (particularly, fluorine), C,-C,-aJkoxy, phenoxy, CVCjo-phenylalkoxy and C2-Cj-acy3oxy, or represent C,-C7-acyl, C6-C,2-aryl or optionally substituted carbamoyl, or represent -(CH^ -OC^O^R6 wherein m denotes an integer of 1 to 32 and R6 represents C,-C,a-al- y], C2-C7-alkenyl, Cj-Cj-alkoxy, Cj-Cy-alky] amino, 20 di(C)-C7-alkyl)amino, C3-C6-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, or =Si(Z)-, wherein Z represents hydrogen, hydroxy or halogen, or represents Ci-Cy-alkyl, C,-C3-alkoxy, , allyl, hydroxy-Cj-C7-alkyl, C]-Craminoalkyl or phenyl, 25 Q represents a group having the following formula:
wherein X1, X2, X3 and X* independently of one another represent hydrogen, amino, hydroxy 30 or halogen, or represent C,-C,-alkyl, Cj- -alkoxy, allyl, phenyl or phenoxy each of which is optionally substituted by nitro or Cj-Cj-alkoxy, or represent C6-C,0-arylthio which is optionally substituted by nitro, amino, Cj-Cβ- alkyl or Cj- -alkoxy, or represent C6-C12-arylamino, Cι-C7-alkylam-no, di(Cr<-V alkyl)amino, C3-C6-cycloalkylamino or a structure of ™» wherein n denotes an integer of 1 or 2 and Y1 represents O, CH2or N-R (R represents -CValkyl or - Cι2-aryl), pharmaceutically acceptable salt, or stereoisomer thereof.
2. The method of claim 1 wherein the pharmaceutically acceptable salt is a salt with sulfuric acid, methanesulfonic acid or hydrohalic acid.
3. The method of claim 1 wherein =i= represents single bond, R1, R2, R3, R7 and R8 independently of one another represent hydrogen, fluorine, hydroxy, C2-C6- alkenyl, C]-C all<yIaπ-ino, CrCs-aminoalkyl, or C,-C3-alkoxy, R4 and Rs independently of one another represent hydrogen, or represent Cj-C4-aIkyl optionally substituted by one or more substituents selected from the group consisting of fluorine, C,-Q,- alkoxy and phenoxy, or represent carbamoyl substituted by -C5- alkyl, or represent -(CH2)m-OC(=O)-R6 wherein m denotes an integer of 1 to 12 and R6 represents Cι-C12-alkyl, C2-C7-alkenyl, C,-C3-alkoxy, Cj-C7-alkylamino, di(Cj-Cτ- alky])amino, C3-C6-cyc3oal--yl, or 3 to 6-membered heterocycle having.1 or 2 hetero atoms selected from a group consisting of nitrogen and oxygen, Y represents -O-, -S-, or -N(Z)-, wherein Z represents hydrogen, hydroxy, Ci-Cj- alkyl, or hydroxy-C,-C7-alkyl, Q represents a group having the following formula:
wherein X1 represents hydrogen, amino, hydroxy or halogen, or represents Cι-C7-a]kyl, Cj- - alkoxy, hydroxy-C]-C7-alkyl or phenoxy each of which is optionally substituted by nitro or Cj- -alkoxy, or lepresents -C)0-arylthio which is optionally substituted by nitro, amino, C,-C6- alkyl or Cj-Q-alkoxy, or represents C6-Cι2-arylamino, Cj-Cr- alkylamino, di(Cι-C7-alkyl)amino, C3-C6-cycloalkylamino or a structure of "3n * wherein n denotes an integer of 1 or 2 and Y1 represents O, CHjOr represents C,-C7-alkyl), and X5, X3 and X4 independently of one another represent hydrogen, amino, hydroxy, halogen, C,-C7-alkyl, -Cj-alkoxy, or Cj-Cj-alkylamino'. 5 , 4. The method of claim 1 , wherein the compound is selected from ({ 1 -[(6-amino-9-y-purin-9-yl)methyl3cyclopropyl} oxy)methylphosphonic acid (Compound 1); 3-[({l-[(6---mino-9-ry-purin-9-yl)methyl3cyclopropyl}oxy)methyl3-8,8-dimethyl-3,7- 0 dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 2); ({ 1 -[(2-amino-6-chloro-9---r-purin-9-yl)methyl3cyclopropyl} oxy)methylphosphonic acid(Compound 3); 3-[({ 1 -[(2---mino-.6-ch]oro-9H-purin-9-yl)methyl]cyclopropyl} oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l -yl pivalate(Compound 4);5 ({l-[(2-amino-6-hydroxy-9-t7-purin-9-yl)methyl3cyclopropyl}oxy)methylphosphonic acid(Compound 5); 3-[({3-[(2-amino-6-hydroxy-9i-'-purin-9-yI)methyI3cyclopropy3}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l -yl pivalate(Compound 6); ({ -[(2---mino-'9H-purin-9-yl)methy-3cyclopropyl} oxy)methylphosphonic acid0 < (Compound 9); 3-[({ 1 -[(2-amino-9 /-purin-9-y])methyl3cyclopropyl} oxy)methyl3-8,8-dimethyl-3,7- dioxo-2,4,6-trioxa-3λJ-phosphanon-l-yl pivalate(Compound 10); ({l-[(2-amino-6-cyc]oproρyIamino-9/f-purin-9-yl)methyJ3cyclopropyl}oxy)methyl phosphonic acid(Compound 11); [(1 - { [2-amino-6-(dimethylamino)-9 -purin-9-yl3methy]} cyclopropyl)oxy3methyl phosphonic acid(Compound 15); 3-{[(3-{[2-amino-6-(dimethylamino)-9-ϋ,-purin-9- yljmethyl} cyclopropyl) oxy]m ethyl} -8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3 λ5- phosphanon-1-yl pivalate(Compound 16); [(1 -{[2-amino-6-(isopropy]amino)-9//-purin-9-yl3methyl}cyclopropyl)oxy]methyl phosphonic acid(Compoυnd 17); 3-{[(3-{[2-amino-6-(isopropy3amino)-9A'-purin-9- y3jmethyl}cyclopropy-)oxyjmethyl}-8,8-dimethy]-3,7-dioxo-2,4,6-trioxa-3λ3- phosphanon-1-yl pivalate(Compound 18); •' ({ 3-[(2,6-diam]'no-9H-purin-9-yl)methyl3cyclopropyl}oxy)methylphosphonic acid (Compound 39); 3-[({l-[(2,6-diamino-9- -ρurin-9-yl)methyl]cyclopropyl}oxy)methyl3-8,8-dimethyl- 3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 20); ({l-[(2-amino-6-methoxy-9-r7-purin-9-yl)methyl3cyclopropyl}oxy)methylphosphonic acid (Compound 21); 3 -[({ 1 -[(2-amino-6-metboxy-9 -purin-9-y-)methyl]cyclopropyl } oxy)methy-3-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 22); ({l-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl3cyclopropyl}oxy)methylphosphonic acid (Compound 23); 3-[({l-[(2-amino-6-ethoxy-9H'-p-ιr-n-9-yl)methyl]cyc]opropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 24); [(l-{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl3methyl}cyclopropyl)oxy] methylphosphonic acid(Compound 31); 8,8-dimethyl-3-{[(l-{[5-methyl-2,4-dioxo-3,4-dihydro-l(2H)-ρyrimidinyl3methyl} cyclopropyl)oxy3methyl}-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 32); [(l-{[2-amino-6-(4-morpholinyl)-9-r-T-purin-9-yl3methyl}cyclopropyl)oxy3methyl phosphonic acid(Compound 37); 3-{[(3-{[2-amino-6-(4-morpholinyl)-9-r-r-purin-9- yl]methyl}cycIopropyl)oxy3methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ3- phosphanon- 1 -yl pivalate(Compound 38); bis(2,2,2-trifluoroethyl) ({ 1 -[(2-amino-6-hydroxy-9-r-?'-purin-9-yl)methyl3cyclo propyl} oxy)methylphosphonate(Compound 45); bis(2,2s2-trifluoroethyl) ({l-[(2---mino-6-chloro-9H-ρurin-9-yl)methyl]cyclopropyl} oxy)methylphosphonate(Compound 46); bis(2,2,2-triflυoroethyl) ({ 1 -[(2,6-diamino-9H-puτin-9-yl)methyl3cyclopropyl}oxy) methyIphosphonate(Compound 47); bis(2,2,2-trifluoroethyl) ({l-[(6-amino-9i/-purin-9-yl)methyl3cyclopropyl}oxy) methylphosphonate(Compound 48); bis(2,2,2-trifluoroethyl) ({l-[(2-ammo-9.#-purin-9-yl)methyI3cyclopropyl}oxy) methylphosphonate(Compound 49); bis(2,2,2-trifluoroethyl) ({ 1 -[(2---mino-6-dimethy]amino-9H-purin-9-yI)methy-3 cyclopropyl} oxy)methylphosphonate(Compound 52); bis(2,2.2-trifluoroethyl) ({ ] -[(2---mino-6-isopropyJamino-9i-'-purin-9-yl)methyl3 cyclopropyl} oxy)mεthylphosphonate(Compound 53); bis(2,2,2-trifluoroethyl) ({ 1 -[(2-a-τ-ino-6-methoxy-9H-purin-9-yl)methyl3cyclo propyl} oxy)methylphosphonate(Compound 54); bis(2,2,2-trifluoroethyl) [(l-{[2-amino-6-(4-morpholinyl)-9_V-purin-9-yl]methyl} cyclopropy-)oxy3methylphosphonate(Compound 58); bis(2,2,2-trifluoroethyl) [(l-{[2-amino-6-(phenylsulfanyl)-9^r-purin-9-yl3methyl) cyclopropyl)oxy3methylphosphonate(Compound 61); bis(2,2,2-trifluoroethyl) { [1 -({2-amino-6-[(4-methylphenyl)sulfanyl3-9-r7-purin-9-yl} methyl)cyclopropyl3oxy}methylphosphonate(Compound 62); bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9flr-purin-9- yl}methyl)cyclopropyl3oxy}methylphosphonate(Compound 63); bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-nitrophenyl)sulfanyl3-9-r7-purin-9-yl} methyl)cyclopropyl3oxy] methylphosphonate(Compound 64); [(1 - { [2-an-ino-6-(phenylsulfanyl)-9-Y-purin-9-yl3-nethyl} cyclopropyl)oxy]methyl phosphonic acid(Compound 65); {[l-({2-armno-6-[(4-memylpheny])-nilfanyl]-9---jr-p -rin-9- yl}methyl)cyclopropyl]oxy}methylphosρhonic acid(Compound 66); 3-({[H{2-amino-6-[(4-methylphenyl)su]fanyl3-9Λ,-purin-9-yl}methyl)cyclopropyl3 oxy}methyl)-8,8-dimetbyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate (Compound 68); bis{[(t-butoxycarbonyl)oxy3methyl}({l-[(2-arnino-9-r-r-purin-9-yl)methyl]cyclo propyl} oxy)methylphosphonate(Compound 69); bis{[(isopropoxycarbonyl)oxy3methyl}({l-[(2-amino-9-r-t"-purin-9-yl)methy]3cyclo propyl} oxy)methylphosphonate (Compound 70); bis{[(ethoxycarbonyl)oxy3methy]}({l-[(2--ιmino-9-r7-ptιrin-9- yl)methyl3cyclopropyl}oxy)methylphosphonate (Compound 71); bis{[(isobutoxyc--rbonyl)oxy3methyl}({3-[(2---n-ino-9iir-purin-9-yl)methyl3cyclo propyl}oxy)methylpbosphonate (Compound 72); 3-[({3-[(2-amino-9H-ρurin-9-y])methyl3cyc]opropyl}oxy)methyl3-9-methyl-3,7- dioxo-2,4,6-trioxa-3λ5-phosphadec-l -yl 3-methylbutanoate(Coπ-poυnd 74); 3-[({]-[(2-amino-9H-purin-9-y])methyl3cyclopropy]}oxy)methyl]-8-methyl-3,7- dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl 2-methylpropanoate(Compound 78); 3-({[3-({2-amino-6-[(4-methoxyphenyl)sulfanyl3-9 -r-purin-9- yl}methyl)cyclopropyl3oxy}methyl)-8,8-dimethyI-3,7-dioxo-2,4,6-trioxa-3λs- phosphanon-1-yl pivalate (Compound 79);
3-[({3-[(2-amino-9-ty-purin-9-yl)methy]3cyclopropyl}oxy)methyl3-3,7-dioxo-7-(l- pyrrolidiny])-2,4, 6-trioxa-3λ5- hosphahept-3 -yl 3 -pyrrolidinecarboxylate(Compound 80); 3-[({3-[(2-amino-9H-pυrin-9-yl)methyl]cyclopropyI}oxy)methyl]-3,7-dioxo-7-(l- p-peridinyI)-2.4,6-trioxa-3λ5-phosphabep--l-yl 3-piperidinecarboxylate(Compound si); 3-[({l-[(2-amino-9-rJ-purin-9-yl)methyl]cycIopropyl}oxy)methyl]-7-(4-morpholinyl)- 3,7-dioxo-2,4,6-trioxa-3λ5-phosphahept-l-yl 4-morpholinecarboxylate(Con-pound 82); bis{[(/-butoxycarbonyl)oxy3methyl}[(l-{[2-amino-6-hydroxy-9-r- -purin-9- 5 i yl]methyl}cyclopropyl)oxy3methylphosphonate(Compound 83); bis{t(isopropoxyc--rboπyl)oxy3methyl}[(l-{[2-amino-6-hydroxy-9--i -purin-9-yl] methyl} cyclopropyl)oxy]methylphosphonate(Compound 84); bis{[(isopropoxyc--rbonyl)oxy3-nethyl} {[l-({2---mino-[6-(4- methoxyphenyl)sulfanyl3-9£f-purin-9- yl}methyl)cyclopropyl3oxy}methylphqsphonate(Compound 85); 3-[({ 1 -[(2-amino-6-hydroxy-9H-purin-9-yl)methyl3cyclopropyl} oxy)methyl]-7- cyclopentyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphahept-l-yl cyclop entanecarboxylate (Compound 86); • 3-({tl-({2-amino-[6-(4-nitrophenyl)sulfanyl3-9i-'-purin-9- yl} methyI)cycIopropyl3oxy} methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ3- phosphanon-l-yl pivalate (Compound 87); bis{[(isopropoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]- 9 -purin-9-yl}methyl)cyclopropyl3oxy}methylphosphonate(Cornpound 88); bis{[(isopropoxyc--rbonyl)oxy]methyl}({l-[(6---r--ino-9-r-?-purin-9-yl)methyl3cyclo ' propyl} oxy)methylphosphonate(Compound 89); 3-[({l-[(6-amino-9-ry-purin-9-yl)methyl]cyclopropyl}oxy)methyl3-9-methyl-3,7- dioxo-2,4,6-trioxa-3λs-phosphadec-l -yl 3-methylbutanoate(Compound 90); 3-[({3-[(6-amino-9H-ρurin-9-y])methyl3cyclopropyl}oxy)methyl3-7-cycIopentyl-3,7- dioxo-2,4.6-trioxa-3λs-phosphahept-3-yl cyclopentanecarboxylate(Compound 91); bis{[(t-butoxycarbonyl)oxy]methyl}{[3-({2-amino-[6-(4-methoxyphenyl)sulfanylJ- 9H-purin-9-yl} ethyl)cyclopropyl3oxy} ethylphosphonate(Compound 92); bis{[(t-butoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl3-9-f3- purin-9-yl}methyl)cyclopropy]3oxy}methy3phosphonate(Compound 93); {[3-({2-amino-[6-(4-nitrophenyl)su3fanyl3-9-y-purin-9-yl}methyl)cyclopropyl3oxy} methylphosphonic acid(Compound 95); {[3-({2-amino-[6-(4-methoxypheny3)su]fanyl3-9- -purin-9-yl}methyl)cyclopropyl] oxy} methylphosphonic acid(Compound 96); ({]-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl3-2-methylcyclopropyl}oxy)methyl phosphonic acid(Compound 97); ' ({1 -[(2---n-ino-9^-purin-9-yl)methyl3-2-methylcyclopropyl}oxy)methylphosphonic acid(Compound 98); {[3-({2-amino-[6-(4-methoxypheny])sulfanyl3-9 i'-purin-9-yl}methyl)-2- methylcyclopropyljoxy} methylphosphonic acid(Compound 99); {[l-({2-amino-[6-(4-nitrophenyi)sulfanyl]-9-r--purin-9-yl}methyl)-2-methylcyclo propyljoxy} methylphosphonic acid(Compound 100); {[l-({2-amino-[6-(4-methylphenyl)sulfanyl3-9 -purin-9-yl}methyl)-2-methyicyclo propyl}oxy} methylphosphonic acid(Compound 101); ({l-[(2,6-d3amino-9izr-purin-9-y])methyl3-2-methylcyclopropy]}oxy)methyl phosphonic acid(Compound 102); ({l-[(6-amino-9-rϊ-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic acid(Compound 103); 3-[({l-[(2-amino-6-hydroxy-9-9r-purin-9-yl)methyl]-2-methylcyclopropyl}oxy) methylJ-S.S-dimethyl-S^-dioxo^Λe-trioxa-Sλ^phosphanon-l-yl pivalate (Compound 105); 3-[({l-[(2-amino-9ΛT-purin-9-y])methyl]-2-methylcyclopropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate(Compound 106); 3-[({l-[(6-amino-9i-'-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl3-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3 λ5-phosphanon-l-yl pivalate(Compound 107); 3-({[l-({2-amino:6-[(4-methoxyphenyl)sulfanyl3-9-f-('-purin-9-yl}methyl)-2-ιnethyl cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 108); bis{[(isopropoxycarbonyl)oxy]methyl}[(l-{[2-amino-6-hydroxy-9-rϊ-purin-9-yl3 methyl}-2-methylcyclopropyl)oxy3methylphosphonate(Compound 109); bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(2-am-no-9-r-?-purin-9-yl)methyl3-2- methylcycloρropyl}oxy)methylphosphonate(Compound 110); bis{[(isopropoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4- methoxyphenyJ)sulfany-]-9 -purin-9-yl}methyI)-2- methylcyclopropyl]oxy}methy]phosphonate(Compound 112); bis{[(t-butoxycarbonyl)oxy]methyl}{[l-({2-amino-f6-(4-methoxyphenyl)sulfanyl]- 9-r-T-purin-9-yI} methyl)-2-methylcycIopropyl]oxy}methylphosphonate(Compound 113); bis(2,2,2-trifluoroethyl) {[l-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9--f-purin-9- yl} methyl)-2-methylcyc3opιoρyl]oxy}methy]phosphonate(Compound 114); bis(2,2,2-trifluoroethyl) { [ 1 -({2-amino-6-[(4-nitropheny3)sulfany]]-9Λ'-purin-9-yl} methyl)-2-methylcyc]opropyl]oxy}methy]phosphonate(Compound 115); bι's{[(t-butoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9Λ'- purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosρhonate(Compound 116); bis{[(isopropoxycarbonyl)oxy]methyl}{[l-({2-amino-[6-(4-nitrophenyl)sulfanyl]- 9Ar-ρurin-9-y]}methyl)-2-methylcyclopropy]]oxy}methy]phosphonate(Compound 117); 3-({[l-({2-amino-6-[(4-nitrophenyl)εulfanyl]-9-^-purin-9-yl}methyl)-2-methylcyclό propyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosρhanon-l-yl pivalate(Compound 118); ({l-[(2---mino-6-hydroxy-9/ϊr-purin-9-yl)methyl]cyclopropyl}amino)methyl phosphonic acid(Compound 119); ({l-[(2-amino-9_ff-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic acid(Compound 120); ({l-[(6-amino-9/-r-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic acid(Compound 121); [ { 1 - [(2- amino-6-hy droxy-9#-purin-9-yl)m ethyl] cyclopropyl} (methyl) amino]methyl phosphonic acid(Compound 122);- [{ - [(6-amino-9-77-purin-9-y])methyl] cyclopropyl} (ethyl)amino]methylphosphonic acid(Compound 125); 3-{[{(l -[(6- amino- 9H-purin-9-yl)methyl]cyclopropyl)(methyl)amino } methyl]-8, 8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 126); bis{[(isopropoxycarbonyl)oxy]methyl}[{l-[(6---mino-9-ff-purin-9-yl)methyl]cyclo propyl} (methyl)amino]methylphosphonate(Compound 127); 3-{[{l-[(2-amino-9i -p--rin-9-yl)methyl]cyc]opropyl}(ethyl)amino]methyl}-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3A5-phosphanon-l-yl pivalate(Compound 129); 2-{l-[(2-amino-6-hydroxy-9i-,-pυrin-9-yl)methyl]cyclopropyl}ethylphosphonic acid(Compound 138); 2-{l-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonic acid(Compound 139); 2-{l-t(6-amino-9-y-pυrin-9-yl)methyl]cyc]opropyl}ethylphosphonic acid(Compound 140);
2-[l-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl] ethylphosphonic acid(Comρound 141); 2-{ 1 -[(2-amino-6-hydroxy-9 -purin-9-y])methyl]cyclopropyl}propylphosphonic acid(Compound 142);
2-{ 1 -[(6-amino-9. -pυrin-9-yl)methy-]cyc]opιopyl}propy3phosphonic acid
(Compound 143);
2-{l-[(2---mino-9-y-purin-9-yl)methyl]cyc3opropyl}propylphosphonic acid
(Compound 344); 3-(2-{ 1 -[(6---mino-9H-purin-9-yl)methy]]cyc]opιoρyl}propyl)-8,8-dimethyl-3,7- dioxo~2,4,6-trioxa-3λi-phosphanon-l-yl pivalate(Compound 145); ({ 1 -[(2-amino-6-hydroxy-9/ -purin-9-yl)methyl]-2,2-dimethylcycIoproρyl} oxy) methylphosphonic acid(Compound 146); ({l-[(2-amino-9Hrpurin-9-yl)methy]]-2,2-dimethylcyclopropyl}oxy)methyl phosphonic acid(Compound 147); ({l-[(6-amino-9-r-r-purin-9-yl).methyl]-2,2-d5methylcyclopropyl}oxy)methyl phosphonic acid(Compound 148); 3-[({l-[(2-amino-6-hydroxy-9-r7-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy) methyl]-8,8-dirnethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosphanon-l-yl pivalate (Compound 149); 3 - [({ 1 -[(2-amino-9#-purin-9-y-)me-hyJ3-2,2-dimethylcyclopropyl} oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-l-yl pivalate(Compound 150); 3-[({l-[(6-amino-9--/-purin-9-y3)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8- dimethyl-3,7-dioxo-2,4,6-trioxa-3λs-phosph--non-l-yl pivalate(Compound 151); bis{[(isopropoxycarbonyl)oxy]methyl}({l-[(6-amino-9-9r-purin-9-yl)methyl]-2,2- dimethylcyclϋpropy]}oxy)methylphosphonate(Compound 152); and bis{ t(iεopropoxycarbonyl)oxy]methyl} [(l-{[2-amino-6-hydroxy-9 /-purin-9-yl3 methyl}-2,2-dJmethylcyclopropyl)oxy]methylphosphonate(Compound 153).
5. The method of claim 1 wherein — represents single bond, R1, R3, R7 and R* independently of one another represent hydrogen, R! represents hydrogen or methyl, R4 and R5 independently of one another represent t-butylcarbonyloxymεthyl, isopropoxycarbonyloxymethyl or 2,2,2-trifluoroethyl, Y represents -O-, Q represents
hydrogen, hydroxy, ethoxy, 4-methoxyphenyIthio or 4-nitrophenylthio, and X2 represents amino.
6- The method of claim 6 wherein R4 and R5 are t-butylcarbonyloxymethyl and X1 is hydrogen or hydroxy.
7. The method of claim 1, further comprising at least one additional therapeutic agent.
8. The method of claim 7, wherein the additional therapeutic agent is an antiviral agent.
9. The method of claim 1, wherein the patient is a mammal.
30. The method of claim 9, wherein the mammal is a human.
EP05723285A 2004-02-17 2005-02-17 Nucleoside phosphonate derivatives useful in the treatment of hiv infections Withdrawn EP1715873A1 (en)

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